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US8329727B2 - Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment - Google Patents

Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment Download PDF

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US8329727B2
US8329727B2 US12/577,865 US57786509A US8329727B2 US 8329727 B2 US8329727 B2 US 8329727B2 US 57786509 A US57786509 A US 57786509A US 8329727 B2 US8329727 B2 US 8329727B2
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Steven S. Bondy
Eric Davis Dowdy
Choung U. Kim
David A. Oare
Johan Neyts
Vahid Zia
Gerhard Pürstinger
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Katholieke Universiteit Leuven
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Katholieke Universiteit Leuven
Gilead Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a series of novel imidazo[4,5-c]pyridine compounds, processes for their preparation, their use to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses belonging to the family of the Flaviviridae and Picomavitidae and more preferably infections with hepatitis-C-virus (HCV).
  • HCV hepatitis-C-virus
  • the family of the Flaviviridae consists of 3 genera, the pestiviruses, the flaviviruses and the hepaciviruses and also contains the hepatitis G virus (HGV/GBV-C) that has not yet been assigned to a genus.
  • Pestiviruses such as the Classical Swine Fever Virus (CSFV), the Bovine Viral Diarrhea Virus (BVDV) and the Border Disease Virus (BDV) cause infections of domestic livestock (respectively pigs, cattle and sheep) and are responsible for significant economic losses world-wide.
  • CSFV Classical Swine Fever Virus
  • BVDV Bovine Viral Diarrhea Virus
  • BDV Border Disease Virus
  • BVDV the prototypic representative of the pestivirus genus is ubiquitous and causes a range of clinical manifestations, including abortion, teratogenesis, respiratory problems, chronic wasting disease, immune system dysfunction, and predisposition to secondary viral and bacterial infections and may also cause acute fatal disease. Fetuses of cattle can be infected persistently with BVDV, these animals remain viremic throughout life and serve as a continuous source for virus spread in herds.
  • Vaccines are used in some countries with varying degrees of success to control pestivirus disease. In other countries, animal culling and slaughter are used to contain pestivirus disease outbreaks.
  • HCV hepatitis C virus
  • Coxsackie viruses belong to the group of the enterovinuses, family of the Picomaviridae. They cause a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome, a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot-mouth syndrome, pediatric and adult pancreatitis and serious myocarditis.
  • WO 00/20416 WO 00/39127, WO 00/40583, WO 03/007945 A1, WO 03/010140 A2, WO 03/010141 A2, WO 93/02080, WO 93/14072, WO 96/11192, WO 96/12703, WO 99/27929, Akamatsu, et al., New Efficient Route for Solid-Phase Synthesis of Benzimidazole Derivatives”, 4:475-483, J. COMB.
  • An embodiment of the present invention provides compounds having the general formula (A),
  • the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds;
  • R 1 is selected from hydrogen, aryl, heterocyclic, C 1 -C 10 alkoxy, C 1 -C 10 thioalkyl, 1 -C 10 alkyl-amino, C 1 -C 10 dialkyl-amino, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and C 4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R 6 ;
  • Y is selected from single bond, O, S(O) m , NR 11 , or C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, wherein each may optionally include 1 to 3 heteroatoms selected from O, S or N;
  • R 2 and R 4 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C( ⁇ O)R 9 , —C( ⁇ S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, or heterocyclic, provided that when one of R 25 or R 26 is present, then either R 2 or R 4 is selected from ( ⁇ O), ( ⁇ S), and ⁇ NR 27 ;
  • X is selected from C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or N, provided any such heteroatom is not adjacent to the N in the ring;
  • n is any integer from 0 to 2;
  • R 3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl-N(R 10 )—, or heterocyclic, where each said substituent may be optionally substituted with at least one R 17 , provided that for cycloalkenyl the double bond is not adjacent to a nitrogen, and provided R 3 -M-Q is not biphenyl;
  • R 5 is selected from hydrogen; C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C( ⁇ O)R 9 , —C( ⁇ O)OR 9 , —C( ⁇ S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, or heterocyclic;
  • R 6 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halo-alkyl, C 2-18 halo-alkenyl, C 2-18 halo-alkynyl, C 1-18 halo-alkoxy, C 1-18 halo-alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO 2 R 18 , NO 2 , —NR 7 R 8 , C 1-18 haloalkyl, C( ⁇ O)R 18 , C( ⁇ S)R 18 , SH, aryl, aryloxy, arylthio, arylsulfoxide, ary
  • R 7 and R 8 are independently selected from hydrogen, C 1-18 alkyl, C 1-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, heterocyclic, —C( ⁇ O)R 12 ; —C( ⁇ S)R 12 , an amino acid residue linked through a carboxyl group thereof, or where R 7 and R 8 together with the nitrogen form a heterocyclic;
  • R 9 and R 18 are independently selected from hydrogen, OH, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 1-18 alkoxy, —N 15 R 16 , aryl, an amino acid residue linked through an amino group of the amino acid, CH 2 OCHO( ⁇ O)R 9a , or CH 2 OC( ⁇ O)OR 9a where R 9a is C 1 -C 12 alkyl, C 6 -C 20 aryl, C 6 -C 20 alkylaryl or C 6 -C 20 aralkyl;
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C( ⁇ O)R 12 , heterocyclic, or an amino acid residue;
  • R 12 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, or an amino acid residue;
  • R 13 and R 14 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C( ⁇ O)R 12 , —C( ⁇ S)R 12 , or an amino acid residue;
  • R 15 and R 16 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, or an amino acid residue;
  • R 17 is independently M-Q- wherein M is a ring optionally substituted with 1 or more R 19 , and Q is a bond or a liking group connecting M to R 3 having 1 to 10 atoms and optionally substituted with 1 or more R 19 ;
  • R 19 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 2-18 alkenyloxy, C 2-18 alkynyloxy, C 1-18 alkylthio, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO 2 , —NR 20 R 21 , C 1-18 haloalkyl, C 1-18 haloalkyloxy, —C( ⁇ O)R 18 , —C( ⁇ O)OR 18 , —OalkenylC( ⁇ O)OR 18 , —OalkylC( ⁇ O)NR 20 R 21 , —OalkylOC( ⁇ O)R 18 , —C( ⁇ S)R 18 , SH, —C( ⁇ O)N(C 1-6 alkyl), —
  • R 20 and R 21 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C( ⁇ O)R 12 , or —C( ⁇ S)R 12 ;
  • R 22 is selected from hydrogen, —OH, C 1-18 alkyl, C 2-18 alkylenyl, C 1-18 alkoxy, —NR 23 R 24 , aryl, C 3-10 cycloalkyl, and C 4-10 cycloalkenyl;
  • R 23 and R 24 are independently selected from hydrogen, C 1-18 alkyl, or a heterocyclic formed by taking C 2-3 alkyl together with N of R 22 , which heterocyclic is optionally substituted with OH or aryl, or an amino acid residue linked through a carboxyl group of the amino acid;
  • R 25 and R 26 are not present, or are independently selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, aryl, heterocyclic, where each is optionally independently substituted with 1 to 4 of C 1-6 alkyl, C 1-6 alkoxy, halo, CH 2 OH, benzyloxy, and OH; and
  • R 27 is selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)-C 1-6 alkyl, aryl, and aryl C 1-18 alkyl, and
  • Another embodiment of the present invention provides compounds having the general formula (A),
  • the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds;
  • R 1 is selected from hydrogen, aryl, heterocyclic, C 1 -C 10 alkoxy, C 1 -C 10 thioalkyl, C 1 -C 10 alkyl-amino, C 1 -C 10 dialkyl-amino, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and C 4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R 6 ;
  • Y is selected from single bond, O, S(O) m , NR 11 , or C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, wherein each may optionally include 1 to 3 heteroatoms selected from O, S or N;
  • R 2 and R 4 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C( ⁇ O)R 9 , —C( ⁇ S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, or heterocyclic, provided that when one of R 25 or R 26 is present, then either R 2 or R 4 is selected from ( ⁇ O), ( ⁇ S), and ⁇ NR 27 ;
  • X is selected from C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or N, provided any such heteroatom is not adjacent to the N in the ring;
  • n is any integer from 0 to 2;
  • R 3 is a heterocycle optionally substituted with at least one R 17 provided, however, that R 3 optionally substituted with at least one R 17 is not pyridinyl or 5-chlorothienyl, provided that R 3 -MQ is not biphenyl;
  • R 5 is selected from hydrogen; C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C( ⁇ O)R 9 , —C( ⁇ O)OR 9 , —C( ⁇ S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, or heterocyclic;
  • R 6 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, heterocyclic, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halo-alkyl, C 2-18 halo-alkenyl, C 2-18 halo-alkynyl, C 1-18 halo-alkoxy, C 1-18 halo-alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO 2 R 18 , NO 2 , —NR 7 R 8 , C 1-18 haloalkyl, C( ⁇ O)R 18 , C( ⁇ S)R 18 , SH, aryl, aryloxy, arylthio, arylsulfox
  • R 7 and R 8 are independently selected from hydrogen, C 1-18 alkyl, C 1-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, heterocyclic, —C( ⁇ O)R 12 ; —C( ⁇ S)R 12 , an amino acid residue linked through a carboxyl group thereof, or where R 7 and R 8 together with the nitrogen form a heterocyclic;
  • R 9 and R 18 are independently selected from hydrogen, OH, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 1-18 alkoxy, —NR 15 R 16 , aryl, an amino acid residue linked through an amino group of the amino acid, CH 2 OCH( ⁇ O)R 9a , or CH 2 OC( ⁇ O)R 9a where R 9a is C 1 -C 12 alkyl, C 6 -C 20 aryl, C 6 -C 20 alkylaryl or C 6 -C 20 aralkyl;
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C( ⁇ O)R 12 , heterocyclic, or an amino acid residue;
  • R 12 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, or an amino acid residue;
  • R 13 and R 14 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C( ⁇ O)R 12 , —C( ⁇ S)R 12 , or an amino acid residue;
  • R 15 and R 16 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, or an amino acid residue;
  • R 17 is independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halogenated alkyl, C 2-18 halogenated alkenyl, C 2-18 halogenated alkynyl, C 1-18 halogenated alkoxy, C 1-18 halogenated alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, CO 2 H, CO 2 R 18 , NO 2 , NR 7 R 8 , haloalkyl, C( ⁇ O)R 18 , C( ⁇ S)R 18 , SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsul
  • R 19 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 2-18 alkenyloxy, C 2-18 alkynyloxy, C 1-18 alkylthio, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO 2 , —NR 20 R 21 , C 1-18 haloalkyl, C 1-18 haloalkyloxy, —C( ⁇ O)R 18 , —C( ⁇ O)OR 18 , —OalkenylC( ⁇ O)OR 18 , —OalkylC( ⁇ O)NR 20 R 21 , —OalkylOC( ⁇ O)R 18 , —C( ⁇ S)R 18 , SH, —C( ⁇ O)N(C 1-6 alkyl), —
  • R 20 and R 21 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C( ⁇ O)R 12 , carboxylester-substituted heterocyclic or —C( ⁇ S)R 12 ;
  • R 22 is selected from hydrogen, —OH, C 1-18 alkyl, C 2-18 alkenyl, C 1-18 alkoxy, —NR 23 R 24 , aryl, C 3-10 cycloalkyl, and C 4-10 cycloalkenyl;
  • R 23 and R 24 are independently selected from hydrogen, C 1-18 alkyl, or a heterocyclic formed by taking C 2-3 alkyl together with N of R 22 , which heterocyclic is optionally substituted with OH or aryl, or an amino acid residue linked through a carboxyl group of the amino acid;
  • R 25 and R 26 are not present or are independently selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, aryl, heterocyclic, where each is optionally independently substituted with 1 to 4 of C 1-6 alkyl, C 1-6 alkoxy, halo, CH 2 OH, benzyloxy, and OH; and
  • R 27 is selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)-C 1-6 alkyl, aryl, and aryl C 1-18 alkyl, and
  • An embodiment of the present invention provides compounds having the general formula (A),
  • the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds;
  • R 1 is selected from hydrogen, aryl, heterocyclic, C 1 -C 10 alkoxy, C 1 -C 10 thioalkyl, C 1 -C 10 alkyl-amino, C 1 -C 10 dialkyl-amino, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, and C 4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R 6 ;
  • Y is selected from single bond, O, S(O) m , NR 11 , or C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene, wherein each may optionally include 1 to 3 heteroatoms selected from O, S or N;
  • X is selected from C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or N, provided any such heteroatom is not adjacent to the N in the ring;
  • n is any integer from 0 to 2;
  • R 3 is a heterocycle optionally substituted with at least one R 17 , provided R 3 -M-Q is not biphenyl;
  • R 5 is selected from hydrogen; C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, halogen, —OH, —CN, —NO 2 , —NR 7 R 8 , haloalkyloxy, haloalkyl, —C( ⁇ O)R 9 , —C( ⁇ O)OR 9 , —C( ⁇ S)R 9 , SH, aryl, aryloxy, arylthio, arylalkyl, C 1-18 hydroxyalyl, C 3-10 cycloalkyl, C 3-10 cycloalkyloxy, C 3-10 cycloalkylthio, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, or heterocyclic;
  • R 6 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 1-18 alkylthio, C 1-18 alkylsulfoxide, C 1-18 alkylsulfone, C 1-18 halo-alkyl, C 2-18 halo-alkenyl, C 2-18 halo-alkynyl, C 1-18 halo-alkoxy, C 1-18 halo-alkylthio, C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO 2 R 18 , NO 2 , —NR 7 R 8 , C 1-18 haloalkyl, C( ⁇ O)R 18 , C( ⁇ S)R 18 , SH, aryl, aryloxy, arylthio, arylsulfoxide, ary
  • R 7 and R 8 are independently selected from hydrogen, C 1-18 alkyl, C 1-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, heterocyclic, —C( ⁇ O)R 12 ; —C( ⁇ S)R 12 , an amino acid residue linked through a carboxyl group thereof, or where R 7 and R 8 together with the nitrogen form a heterocyclic;
  • R 9 and R 18 are independently selected from hydrogen, OH, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 1-18 alkoxy, —NR 15 R 16 , aryl, an amino acid residue linked through an amino group of the amino acid, CH 2 OCH( ⁇ O)R 9a , or CH 2 OC( ⁇ O)OR 9a where R 9a is C 1 -C 12 alkyl, C 6 -C 20 aryl, C 6 -C 20 alkylaryl or C 6 -C 20 aralkyl;
  • R 10 and R 11 are independently selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, aryl, —C( ⁇ )R 12 heterocyclic, or an amino acid residue;
  • R 12 is selected from the group consisting of hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, or an amino acid residue;
  • R 13 and R 14 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C( ⁇ O)R 12 , —C( ⁇ S)R 12 , or an amino acid residue;
  • R 15 and R 16 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, or an amino acid residue;
  • R 17 is M-Q-, wherein M is a C 3-10 cycloalkyl optionally substituted with 1 or more R 19 , and Q is a bond, or C 1-10 alkyl optionally substituted with 1 or more R 19 ;
  • R 19 is selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, C 1-18 alkoxy, C 2-18 alkenyloxy, C 2-18 alkynyloxy, C 1-18 alkylthio, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, C 4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO 2 , —NR 20 R 21 , C 1-18 haloalkyl, C 1-18 haloalkyloxy, —C( ⁇ O)R 18 , —C( ⁇ O)OR 18 , —OalkenylC( ⁇ O)OR 18 , —OalkylC( ⁇ O)NR 20 R 21 , —OalkylOC( ⁇ O)R 18 , —C( ⁇ S)R 18 , SH, —C( ⁇ O)N(C 1-6 alkyl), —
  • R 20 and R 21 are independently selected from hydrogen, C 1-18 alkyl, C 2-18 alkenyl, C 2-18 alkynyl, aryl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, —C( ⁇ O)R 12 , or —C( ⁇ S)R 12 ;
  • R 22 is selected from hydrogen, —OH, C 1-18 alkyl, C 2-18 alkenyl, C 1-18 alkoxy, —NR 23 R 24 , aryl, C 3-10 cycloalkyl, and C 4-10 cycloalkenyl;
  • R 23 and R 24 are independently selected from hydrogen, C 1-18 alkyl, or a heterocyclic formed by taking C 2-3 alkyl together with N of R 22 , which heterocyclic is optionally substituted with OH or aryl, or an amino acid residue linked through a carboxyl group of the amino acid;
  • R 25 and R 26 are not present, or are independently selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, aryl, heterocyclic, where each is optionally independently substituted with 1 to 4 of C 1-6 alkyl, C 1-6 alkoxy, halo, CH 2 OH, benzyloxy, and OH; and
  • R 27 is selected from hydrogen, C 1-18 alkyl, C 3-10 cycloalkyl, (C 3-10 cycloalkyl)-C 1-6 alkyl, aryl, and aryl C 1-18 alkyl, and
  • Yet another embodiment of the present invention provides compounds having the formula (B),
  • the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds; and R 1 , R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , X and Y are as disclosed above.
  • An embodiment of the present invention provides compounds of the formula (B) wherein Y is a single bond, and R 1 is aryl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein X is C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is heterocyclic.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is heterocyclic substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein Y is a single bond, and R 1 is phenyl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (B) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is phenyl.
  • Yet another embodiment of the present invention provides compounds having the formula (C),
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 25 , R 26 , X and Y are as disclosed above.
  • An embodiment of the present invention provides compounds of the formula (C) wherein Y is a single bond, and R 1 is aryl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein X is C 1 -C 10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is heterocylic.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is heterocyclic substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein Y is a single bond, and R 1 is phenyl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is aryl.
  • Another embodiment of the present invention provides compounds of formula (C) wherein R 3 is isoxazole substituted with R 17 where Q is a bond and M is phenyl.
  • the compounds of formula (A) are optionally combined with pharmacologically acceptable excipients.
  • the compounds of formula (A) are administered in therapeutically effective amounts to subjects (humans or animals) in need of antiviral therapy, in particular for inhibiting the infection, growth or replication of Flaviviridae and Picornaviridae, especially BVDV, HCV and Coxsackie virus.
  • the invention further relates to a method of screening antiviral compounds which comprises providing a compound of formula (A) and determining the anti-viral activity of said compound.
  • a metabolite of the compounds of formula (A) made by the process of administering a compound of formula (A) to a subject and recovering the metabolite from the subject.
  • the invention also comprises a method for structure-activity determination of analogues of formula (A) compounds
  • Alkyl means saturated hydrocarbon moiety where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions.
  • the acyclic portion may contain 1 to 3 carbon atoms, and each ring may contain 3 to 6 carbon atoms (for example, 3-methylcyclohexyl).
  • cycloalkyl refers to the saturated hydrocarbon moieties that are cyclic.
  • alkyl examples include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu) 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-methyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl and
  • Alkenyl means a hydrocarbon moiety with at least one site of double bond unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions.
  • the acyclic portion may contain 1 to 3 carbon atoms, and each cyclic portion may contain 3 to 6 carbon atoms.
  • a site of double bond unsaturation maybe in a acyclic portion, a cyclic portion. In the instance of a moiety having a combination of acyclic and cyclic portions, there may be a site of double bond unsaturation in each of the portions.
  • the term “cycloalkenyl” refers to the double bond unsaturated hydrocarbon moieties that are cyclic.
  • alkenyl include, but are not limited to, ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ), 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • the double bond optionally is in the cis or trans configuration.
  • Alkynyl means a hydrocarbon moiety with a least one site of triple bond unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions.
  • the acyclic portion may contain contain 1 to 3 carbon atoms, and each cyclic portion may contain 7 or more carbon atoms.
  • cycloalkenyl refers to triple bond unsaturated hydrocarbon moieties that are cyclic.
  • alkynyl include, but are not limited to, —C ⁇ CH, —CH 2 C ⁇ CH, —CH 2 C ⁇ C-cyclohexyl, or —CH 2 -cycloheptynyl.
  • alkyl, alkenyl and alkynyl groups refers to such groups with at least 2 sites of substitution.
  • polyvalent hydrocarbon radicals include, but are not limited to, methylene (—CH 2 —) 1,2-ethylene (—CH 2 CH 2 —), 1,3-propylene (—CH 2 CH 2 CH 2 —), 1,4-butylene (—CH 2 CH 2 CH 2 CH 2 —), 1,2-ethylene (—CH ⁇ CH—), —C ⁇ C—, propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • Aryl means an aromatic hydrocarbon containing 1 or more rings, generally 1, 2 or 3, with 4 to 6 carbon atoms in each, ordinarily 5 or 6 carbon atoms.
  • Arylalkyl means an alkyl, alkenyl or alkynyl radical, respectively, in which one of the hydrogen atoms, typically a terminal or sp3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylehian-1-yl and the like.
  • carbocycles optionally are found as single rings or multiple ring systems. Ordinarily the hydrocarbons of the compounds of formula (A) are single rings. Monocyclic carbocycles generally have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • the number of carbon atoms is unspecified for a hydrocarbon, typically the number of carbon atoms will range from 1 to 18, except that the number of carbons typically will range from 2 to 18 for unsaturated hydrocarbons and from 6 to 10 for aryl.
  • Heterocyclic or “heterocycle” means any 4, 5, 6, 7, 8 or 9 membered single or fused ring system containing one or more heteroatoms selected from the group consisting of O, N or S. Heterocycles optionally are entirely aromatic, entirely saturated, or contain 1 or more intra-ring sites of unsaturation, typically double bonds. Multiple heterocyclic rings (one or more of which contains a heteroatom) are bridged or spiro. Generally, the heterocyclic rings will be aromatic, and usually they are single rings.
  • heterocycles include oxazacyloalkyl, morpholinyl, dioxacycloalkyl, thiacycloalkenyl, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydro
  • Carbon bonded heterocycles typically are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrminidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • Nitrogen containing heterocycles are bonded at nitrogen or a carbon, typically a carbon atom. These include, for example, position 1 of aziridine, 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-piperidinyl, 2-pyrroline, 3-pyrroline, 2-imidazoline, 3-imidazoline, 9-carbazole, 4-morpholine, 9-alpha or ⁇ -carboline, 2-isoindole, 2-pyrazoline and 3-pyrazoline, and by analogy, azetidine, pyrrole, pyrrolidine piperidine, piperazine, indole, pyrazoline, indoline, imidazole, imidazolidine, 1H-indazole and isoindoline. These and other N-containing heterocycles are well-known to those skilled in the art, and their linkage sites are a matter of discretion.
  • Sulfur containing heterocycles are bonded through carbon or sulfur. They include oxidized states such as —S( ⁇ O)( ⁇ O). In general, they are linked in the compounds of formula (A) analogous to N-containing heterocycles.
  • Alkoxy”, “cycloalkoxy”, “aryloxy”, “arylalkyloxy”, “oxy heterocycle”, “thioalkyl”, “thiocycloalkyl”, “arylthio”, and “arylalkylthio” means substituents wherein an alkyl, cycloalkyl, aryl, or arylalkyl, respectively, are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
  • Halogen means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
  • the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state—any and all protonated forms of the compounds are intended to fall within the scope of the invention.
  • Amino-acid refers to a radical derived from a molecule having the chemical formula H 2 N—CHR 28 —COOH, wherein R 28 is a side group of a naturally-occurring or known synthetic amino-acid.
  • the amino acids optionally are substituted with hydrocarbon typically of 1 to 8 carbons at one or more carboxyl or amino groups, whether those groups are on the side chain or are free after linking the amino acid to the remainder of the compound of this invention.
  • the amino acid residue is a hydrophobic residue such as mono- or di-alkyl or aryl amino acids, cycloalkylamino acids and the like.
  • the residue does not contain a sulhydryl or guanidino substituent.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included.
  • oxie of any site in the parental molecule is substituted with an amino acid, although it is within scope of this invention to introduce amino acids at more than one permitted site.
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid are bonded to the remainder of the molecule, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates).
  • amino acid esters optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH >10) conditions.
  • they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • R 28 usually is C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with amino, carboxyl, amide, carboxyl (as well as esters, as noted above), hydroxyl, C 6 -C 7 aryl, ganidinyl, imidazolyl, indolyl, sulhydryl, sulfoxide, and/or alkylphosphate.
  • R 28 also is nitrogen to form a proline residue taken together with the amino acid ⁇ .
  • R 28 is generally the side group of the naturally-occurring amino acid disclosed above, for example H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 —CH(CH 3 ) 2 , —CHCH 3 —CH 2 —CH 3 , —CH 2 —C 6 H 5 , —CH 2 CH 2 —S—CH 3 , —CH 2 OH, —CH(OH)—CH 3 , —CH 2 —SH, —CH 2 —C 6 H 4 OH, —CH 2 —CO—NH 2 , —CH 2 —CH 2 —CO—NH 2 , —CH 2 —COOH, —CH 2 —CH 2 —COOH, —(CH 2 ) 4 —NH 2 and —(CH2) 3 —NH—C(NH 2 )—NH 2 .
  • R 28 also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-y
  • R 1 is generally aryl or aromatic heterocyle substituted with 1, 2 or 3 R 6 wherein R 6 is halogen, C 1-18 alkoxy; or C 1-18 haloalkyl. Typically, R 1 is phenyl substituted with 1, 2 or 3 halogens, usually fluoro.
  • Y generally is a single bond, O, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene or one of said groups containing 1 to 3, usually 1, heteroatoms selected from O, S or NR 11 .
  • Examples include —O(CH 2 ) 1-5 —, —(CH 2 ) 1-4 —O—(CH 2 ) 1-4 —, S—(CH 2 ) 1-5 —, —(CH 2 ) 1-4 —S—(CH 2 ) 1-4 —, —NR 11 —(CH 2 ) 1-5 —, —(CH 2 ) 1-4 —NR 11 —(CH 2 ) 1-4 or C 3-10 cycloalkylidene.
  • Y is —OCH 2 —, —CH 2 O—, C 1-2 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, O or a bond, but usually a bond.
  • YR 1 is not any one of H, an unsubstituted C 3-10 cycloalkyl or C1-C6 alkyl.
  • YR 1 is halo or halomethyl-substituted (typically trihalomethyl) phenyl (and usually 1 to 2 substituents in ortho or meta).
  • X usually is alkylene, alkynylene or alkenylene, typically alkylene, or said hydrocarbons having an intrachain heteroatom, typically O or S.
  • Examples include —CH 2 —, —CH(CH 3 )—, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 , —(CH 2 ) 2-4 —O—(CH 2 ) 2-4 —, —(CH 2 ) 2-4 —S—(CH 2 ) 2-4 —, —(CH 2 ) 2-4 —NR 10 —(CH 2 ) 2-4 —, C 3-10 cycloalkylidene, C 2-6 alkenylene (such as —CH ⁇ CH—CH 2 —) and C 2-6 alkynylene.
  • X is methylene.
  • R 3 generally is aryl or a heterocycle, typically an aromatic heterocycle.
  • the heterocycle generally will contain 1, 2 or 3 N, S or O atoms in the ring, usually is linked to X through a ring carbon atom and typically contains 4 to 6, usually 5, total ring atoms.
  • the R 3 aryl or heterocycle ordinarily is substituted with 1, 2 or 3, usually 1, R 17 .
  • R 3 optionally is not indolyl.
  • R 17 When R 3 is substituted with R 17 then R 17 typically is aryl or a heterocycle further substituted with 1 or more, usually 1, 2 or 3, R 19 .
  • R 17 is M-Q in some embodiments of the invention.
  • M is a ring. This means any cyclic organic structure, whether carbocyclic or heterocyclic, and whether saturated, unsaturated or aromatic or single or fused ring systems. M is chosen from rings that are structurally stable in biological systems. In general, M is a aryl or aromatic heterocycle where heterocycle is defined above.
  • Q is a spacer group, and is not critical. Typically it is not cyclic and contains from no to 3 atoms, generally C, O or S, usually C or O.
  • R 17 typically is selected from the group consisting of C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 7-10 cycloalkynyl, halogen, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy (optionally an benzyloxy); arylalkylthio (optionally a benzylthio); a heterocycle; C 1-18 hydroxyalkyl, but typically is an aryl or a heterocycle, and where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, or heterocycle is optionally substituted with 1 or more R 19 .
  • R 17 generally is positioned dist
  • R 9 and R 18 typically are H, OH or alkyl.
  • R 18 optionally is not NR 15 R 16 .
  • R 5 typically is H.
  • R 6 generally is halogen. Optionally, R 6 is not C(O) R 18 .
  • R 7 , R 8 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 20 , R 21 , R 23 and R 24 typically are independently H or C 1-18 alkyl.
  • R 12 and R 22 typically are independently OH or alkyl.
  • R 19 usually is H; C 1-18 alkyl; C 2-18 alkenyl; C 2-18 alkynyl; C 1-18 alkoxy; alkenyloxy; alknyloxy; C 1-18 alkylthio; C 3-10 cycloalkyl; C 4-10 cycloalkenyl; C 4-10 cycoalkynyl; halogen; OH; CN; cyanoalkyl; NO 2 ; NR 20 R 21 ; haloalkyl; haloalkyloxy; C( ⁇ O)R 18 ; C( ⁇ O)OR 18 ; OalkenylC( ⁇ O)OR 18 ; —OalkylC( ⁇ O)NR 20 R 21 ; aryl; heterocycle; —OalkylOC( ⁇ O)R 18 ; C( ⁇ O)N(C 1-6 alkyl), N(H)S(O)(O)(C 1-6 alkyl); arylalkyloxy; aryloxy;
  • R 25 and R 26 usually are not present but if they are then typically they are cyclopentyl or cyclohexyl. If the compound is substituted at R 25 or R 26 , either R 2 or R 4 is selected from ( ⁇ O), ( ⁇ S), and ( ⁇ NR 27 ), usually ⁇ O.
  • M typically is an aromatic ring, usually single or two fused rings, and containing 4 to 10 atoms. Usually, M is hydrocarbon, but also optionally comprises 1 to 3 N, O and/or S heteroatoms.
  • Q usually is a hydrocarbon chain, typically a normal or secondary alkylene, which optionally comprises at least one oxy or thio ester. Generally Q is 1 to 6 atoms, usually 1 to 3. Q typically is not substituted with R 19 , but if it is then typically it is substituted with one R 19 . R 19 as substituted on Q usually is halogen, nitro or cyano. Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
  • Haloalkyl or haloalkyloxy typically are —CF3 or —OCF3.
  • the present invention provides a compound of Formula (A) of the following the structure,
  • the present invention further provides a compound of Formula (A) of the following structure,
  • Formula (A) depicts optional single or double bonds. It will be understood that the bonds are present such that the aromatic nature of the nucleus of formula (A) is preserved, i.e., these formulas are intended to embrace all possible tautomers.
  • R 25 or R 26 will be absent if the ring N to which they are bonded as indicated in the formula is linked to a flanking ring carbon atom by a double bond.
  • R 25 or R 26 may be present when the N atom to which it is bonded as indicated in the formula is linked to its flanking carbon atoms by single bonds only; in this case aromaticity is accommodated by other substituents, e.g. where R 2 or R 4 is oxo.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound
  • prodrugs are capable of acting as prodrugs.
  • prodrugs are labile functional groups which separate from an active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process.
  • prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a “prodrug” is thus a covalently modified analog of a therapeutically-active compound.
  • a prodrug moiety of course can be therapeutically active in its own right.
  • Exemplary prodrug moieties include the hydrolytically sensitive or labile esters (—CO 2 R′) of carboxylic acids (—CO 2 H) or other functional groups with an acidic proton which is bound to the imidazo[4,5-c]pyridine compounds of the invention.
  • the R′ group of such hydrolytically sensitive or labile esters may include: (i) acyloxymethyl esters —CH 2 OC( ⁇ O)R 9a ; and (ii) acyloxymethyl carbonates —CH 2 OC( ⁇ O)OR 9a where R 9a is C 1 -C 6 alkyl C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the invention.
  • An exemplary acyloxymethyl ester R group is pivaloyloxymethoxy, (POM) —CH 2 OC( ⁇ O)C(CH 3 ) 3 .
  • An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH 2 OC( ⁇ O)OC(CH 3 ) 3 .
  • Cleavable moieties capable of acting as prodrug functionalities are optionally linked at any tolerant site on the compound of this invention, for example R 3 and any of its substituents.
  • the present invention excludes all compounds expressly disclosed in any prior art reference (to the extent the reference is effective as novelty- or inventive step/obviousness-defeating as the case may be) set forth in this application (as well as any compounds disclosed in any reference patent family member) and and any other compounds over which the claims of this application are not novel or do not posses an inventive step or are obvious under applicable law.
  • the present invention excludes, as required, compounds according to the general formula (A) where
  • any of the substituents X, Y, R 1 , R 2 , R 3 , R 4 , R 5 are a cephalosporin or wherein the substituents X, Y, R 1 , R 2 , R 3 , R 4 , R 5 are an azabicyclo group, more particularly 5-Tia-1-aza-bicyclo[4.2.0]oct-2-en-8-one;
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein (a) Y R 1 is not phenyl para substituted with OH, or (b) is H, an unsubstituted C 3-10 cycloalkyl, or C 1-6 alkyl.
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R 1 is not H, Y is not NR 11 with R 11 C 1-6 alkyl or methyl, and/or YR 1 is not monomethylamino.
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R 1 is a phenyl substituted with 1R 6 , R 6 is C( ⁇ O)R 18 and R 18 is t-butoxy.
  • the compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R 1 is not piperidinyl and is not piperazinyl substituted with methyl.
  • the compounds of this invention exclude those compounds disclosed by WO 2004/005286, in particular the compounds in table 8 thereof.
  • the compounds of this invention optionally exclude those in which XR 3 is the definitional equivalent to the substructure —(CH2)n—Y—C(O)—N(R1)(R2) set forth on column 1, line 49 to column 2 line 38 of U.S. Pat. No. 5,302,601 and the comparable disclosure in any member of the patent family of U.S. Pat. No. 5,302,601, which disclosure is herewith expressly incorporated by reference.
  • the compounds of this invention optionally exclude those in which R 5 contains any of the substituents designated as ⁇ Ar>> in WO 00/39127, in particular aryl, aryl phenoxy, or benzyl.
  • the compounds of this invention optionally do not include the compounds of Example 35 of U.S. Pat. No. 5,302,601, Example 6 of U.S. Pat. No. 4,990,518, Examples 1 to 5 of U.S. Pat. No. 4,988,707, Examples 1-5 of U.S. Pat. No. 5,208,241, Example 39 of U.S. Pat. No. 5,137,896, the azabenzimidazole compound of WO 99/27929, Examples 1-20 and 45 of U.S. Pat. No. 5,227,384, Examples 3 and/or 11 of WO 96/12703 and/or compounds 340A, 347C, 349C, 351C, 355C and/or 356 C of WO 96/11192.
  • the compounds of this invention optionally exclude those in which XR 3 is equivalent to the substructure —(CH 2 )n-Het-C(O)—N(R 1 )(R 2 ) set forth on column 1, line 41 to column 2 line 24 of U.S. Pat. No. 4,990,518.
  • the compounds of this invention do not include the compounds expressly disclosed in the patents listed in the Background of the Invention above, in Chemical Abstracts acc no. 1987:18435 and in Chemical Abstracts acc no. 1983:594812.
  • the compounds of this invention do not include the compounds expressly disclosed in Justus Liebigs Annalen der Chemie (1971), 747, 158-171 or in the Journal of the Chemical Society [section B]: Physical Organic (1966), 4, 285-291.
  • the compounds of this invention exclude those compounds wherein YR 1 is one of the substitutents designated R 13 in column 5, lines 22-38 of U.S. Pat. No. 5,486,525 and/or R 2 and/or R 5 are one of the substituents collectively designated R 14 and R 15 in column 5, lines 38-53 of U.S. Pat. No. 5,486,525.
  • the compounds of this invention exclude the compounds found in any patent family member of any published or issued patent specifically recited in this application.
  • the compounds of this invention optionally also exclude the methylene homologues of the foregoing known compounds excluded from the scope of this invention. It is understood that a compound optionally excluded also includes the salts thereof.
  • the compounds of this invention or the metabolites produced from these compounds in vivo, have a large number of uses. They are useful in immunology, chromatography, diagnostics and therapeutics, among other fields.
  • the compounds of formula (A) are conjugated to immunogenic polypeptides as a reagent for eliciting antibodies capable of binding specifically to the polypeptide, to the compounds or to their metabolic products which retain immunologically recognized epitopes (sites of antibody binding).
  • immunogenic compositions therefore are useful as intermediates in the preparation of antibodies for use in diagnostics, quality control, or the like, or in assays for the compounds of formula (A) or their novel metabolic products.
  • the compounds are useful for raising antibodies against otherwise non-immunogenic polypeptides, in that the compounds serve as haptenic sites stimulating an immune response which cross-reacts with the unmodified conjugated protein.
  • Conjugates of the compounds of formula (A) with immunogenic polypeptides such as albumin or keyhole limpet hemocyanin generally are useful as immunogens.
  • the polypeptides are conjugated at the same sites denoted for amino acids.
  • the metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention
  • the antibodies of this invention will be capable of binding to the unprotected compounds of the invention without binding to the protected compounds.
  • the metabolic products will be capable of binding to the protected compounds and/or the metabolitic products without binding to the protected compounds of the invention, or will be capable of binding specifically to any one or all three.
  • the antibodies desirably will not substantially cross-react with naturally-occurring materials.
  • Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes sufficient to interfere with the assay results.
  • the immunogens of this invention contain the compound of this invention presenting the desired epitope in association with an immunogenic substance.
  • association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above.
  • Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and immunogenic polysaccharides.
  • the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent.
  • a polyfunctional (ordinarily bifunctional) cross-linking agent for the manufacture of hapten immunogens are conventional per se, and any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to the epitope in question as opposed to the immunogenic substance.
  • polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized.
  • the conjugates are prepared in conventional fashion.
  • the cross-linking agents N-hydroxysuccinimide, succinic anhydride or alkN ⁇ C ⁇ Nalk are useful in preparing the conjugates of this invention.
  • the conjugates comprise a compound of the invention attached by a bond or a linking group of 1-100, typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance.
  • the conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage.
  • Animals are typically immunized against the immunogenic conjugates or derivatives and antisera or monoclonal antibodies prepared in conventional fashion.
  • the compounds of this invention are useful as linkers, spacers or affnity (typically hydrophobic) moieties in preparing affinity absorption matrices.
  • the compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity cbromatography separations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl groups are useful in making hydrophobic affinity columns.
  • the compounds herein contain functional groups that are suitable as sites for cross-linking desired substances.
  • affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates.
  • affinity reagents such as hormones, peptides, antibodies, drugs, and the like
  • immobilized enzymes are used to perform catalytic conversions with facile recovery of enzyme.
  • Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
  • the compounds of this invention are labeled with detectable moieties such biotin, radioisotopes, enzymes and the like for diagnostic purposes.
  • detectable moieties such biotin, radioisotopes, enzymes and the like for diagnostic purposes.
  • Suitable techniques for accomplishing the labeling of the compounds of formula (A) are well known and will be apparent to the artisan from consideration of this specification as a whole.
  • one suitable site for labeling is R17 or R19.
  • the compounds of the invention are employed for the treatment or prophylaxis of viral infections such as yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus, but more particularly flaviviral or picornaviral infections, in particular, HCV and BVDV.
  • viral infections such as yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus, but more particularly flaviviral or picornaviral infections, in particular, HCV and BVDV.
  • the therapeutic compound(s) of this invention are administered to a subject mammal (including a human) by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization.
  • the therapeutically effective amount of the compound(s) is a flaviviral or picornaviral growth inhibiting amount. More preferably, it is a flaviviral or picornaviral replication inhibiting amount or a flaviviral or picornaviral enzyme inhibiting amount of the compounds of formula (A).
  • the actual amount will depend upon many factors known to the artisan, including bioavailability of the compound, whether it contains a prodrug functionality, its metabolism and distribution in the subject and its potency, among others. It typically is necessary to determine the proper dosing in the clinical setting, and this is well within the skill of the ordinary artisan.
  • the therapeutically effective amount of the compound(s) of this invention optionally are divided into several sub-units per day or are administered at daily or more than one day intervals, depending upon the pathologic condition to be treated, the patient's condition and the nature of the compound of this invention.
  • the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg . (1984) 22:27 or tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem . (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother . (1984) 25:515-517, using EC 50 for calculating the fractional inhibitory concentration.
  • Suitable anti-viral agents for inclusion in combination antiviral compositions or for coadministration in a course of therapy include, for instance, interferon alpha, ribavirin, a compound falling within the scope of disclosure of EP 1162196, WO 03/010141, WO 03/007945 and WO 03/010140, a compound falling within the scope of disclosure of WO 00/204425, and other patents or patent applications within their patent families, in amounts of 1 to 99.9% by weight compound of this invention, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight as can be readily determined by one skilled in the art.
  • Such co-admmistered agents need not be formulated in the same dosage form as the compound of the invention. They optionally are simply administered to the subject in the course of treatment along with a course of treatment with a compound of formula (A).
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore, for example in the treatment of BVDV.
  • Veterinary carriers are materials useful for the purpose of administering the composition and are excipients which are otherwise inert or acceptable in the veterinary art and are compatible with the compound of this invention. These veterinary compositions maybe administered orally, parenterally or by any other desired route.
  • salts as used herein means the therapeutically active non-toxic salt forms formed by the compounds of formula (A). Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • the compounds of the invention may bear multiple positive or negative charges.
  • the net charge of the compounds of the invention may be either positive or negative.
  • Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained.
  • Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof.
  • any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
  • counter ions e.g., dry salts
  • counter ions e.g., aqueous or organic solutions
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li+, Na+, Ca+2 and Mg+2 and K+.
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g.
  • hydrochloric or hydrobromic acid sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, benzoic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, fumaric, tartaric, pyruvic, maleic, malonic, malic, salicylic (i.e.
  • 2-hydroxybenzoic p-aminosalicylic, isethionic, lactobionic, succinic oxalic and citric acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids, C1-C6 ailylsulfonic, benzenesulfonic, p-toluenesuifonic, cyclohexanesulfamic, and the like.
  • Preferred salts include mesylate and HCl.
  • the compounds of this invention include the solvates formed with the compounds of formula (A) and their salts, such as for example hydrates, alcoholates and the like.
  • the compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • Salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a compound of formula (A). All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • isomers as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formula (A) may possess, but not including position isomers.
  • the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well.
  • the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formula (A) may have one or more chiral centers), as well as the stereochemically pure or enriched isomers. More particularly, stereogenic centers may have either the R- or S-configuration, and double or triple bonds optionally are in either the cis- or trans-configuration.
  • Enriched isomeric forms of a compound of this invention are defined as a single isomer substantially free of the compound's other enantiomers or diastereomers.
  • the term “stercoisomericahy enriched” or “chirally enriched” relates to compounds having a single stereoisomeric proportion of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%.
  • the terms “enantiomerically pure” and “diastereomerically pure” contain undetectable levels of any other isomer.
  • stereoisomers Separation of stereoisomers is accomplished by standard methods known to those in the art.
  • One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing an acidic functionality, such as carboxylic acid and sulfonic acid.
  • enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like
  • an acidic functionality such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts optionally are induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994). Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase.
  • Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives.
  • Commercially available polysaccharide based chiral stationary phases are ChiralCeITM CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and ChiralpakTM AD, AS, OP(+) and OT(+).
  • eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like.
  • an alcohol such as ethanol, isopropanol and the like.
  • the present invention also provides the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. C14 or H3) compound of the invention, administering it parenterally in a detectable dose (e.g.
  • a radiolabelled e.g. C14 or H3
  • metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no antiviral activity of their own.
  • the compounds of the invention optionally are formulated with conventional pharmaceutical carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipiexits” (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the term “pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness.
  • the pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
  • Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals.
  • compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
  • Suitable surface-active agents also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties.
  • Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents.
  • Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C 10 -C 22 ), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil.
  • Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and allylarylsulphonates.
  • Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g.
  • Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms.
  • alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product.
  • corresponding phosphates e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids.
  • Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecitlun type such as e.g.
  • phosphatidylethanolamine phosphatidylserine, pliosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl-choline and their mixtures.
  • Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulfosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol.
  • non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups.
  • Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit.
  • non-ionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethainol.
  • Fatty acid esters of polyethylene sorbitan such as polyoxyethylene sorbitan trioleate
  • glycerol glycerol
  • sorbitan sucrose and pentaerythritol are also suitable non-ionic surfactants.
  • Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals.
  • C8C22 alkyl radical e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like
  • Compounds of the invention and their physiologically acceptable salts may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration may vary with for example the condition of the recipient.
  • the formulations both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) optimally are “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • For infections of the eye or other external tissues e.g.
  • the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
  • the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl paliutate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylceulose, protamne sulfate and the like.
  • the rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl metliacrylate and the other above-described polymers.
  • Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsioas, nanoparticles, nanocapsules and so on.
  • the pharmaceutical composition may require protective coatings.
  • Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
  • each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
  • the compounds of formula (A) are prepared using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further.
  • the processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.
  • the invention also relates to methods of making the compositions of the invention.
  • the compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
  • reaction conditions such as temperature, reaction time, solvents, workup procedures, and the lice, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be ⁇ 100° C. to 200° C.
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to ⁇ 100° C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to ⁇ 100° C.) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
  • treated means contacting, nixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • This means that “treating compound one with compound two” is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
  • “Treating” indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures ( ⁇ 100° C. to 250° C., typically ⁇ 78° C. to 150° C, more typically ⁇ 78° C. to 100° C., still more typically 0° C. to 100° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated.
  • the knowledge of similar reactions known in the art of organic synthesis is used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic sysnthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • alkylating reagents which may be employed in the pyridyl alkylation reaction of Scheme 1.
  • the residue of the alkylating agent is located at the X R 3 site of the compound of this invention.
  • the remainder of the compound will be as found in any of the compounds of examples 2-7.
  • Scheme 2 shows a synthetic route to 5-biarylmethyl-2-phenyl-5H-imidazo[4,5-c]pyridines and 5-benzyl-2-biaryl-5H-imidazo[4,5-c]pyridines.
  • Scheme 3 shows a synthetic route to 5-(alkoxybenzyl)-2-phenyl-5H-imidazo[4,5-c]pyridines and 5-benzyl-2-alkoxybenzyl-5H-imidazo[4,5-c]pyridines.
  • R, R′, and R′′ can be any alkyl benzylic or heterobenzylic groups.
  • Analogous compounds may be synthesized in the same fashion as in the foregoing schemes by varying the starting materials, intermediates, solvents and conditions as will be known by those skilled in the art.
  • Phosphorous pentoxide 24.56 g was dissolved in methanesulfonic acid (165.8 mL) at 50° C. with stirring.
  • methanesulfonic acid 165.8 mL
  • 3,4-diaminopyridine (12.3 g, 0.11 moles) and 2,3-difluorobenzoic acid (19.4 g, 0.12 moles) were added.
  • the reaction mixture was heated to 190° C. for 3 hours. The reaction was done three times.
  • the reaction mixtures was cooled to 50° C. and poured into ice with stirring. At this stage, all three batches were combined
  • the reaction mixture was neutralized by the addition of NaOH with stirring until the pH is 8. Solid material precipitated out of solution, was collected by filtration and air-dried.
  • the material was crystallized by dissolving the material in MeOH with heat, followed by precipitation with water. This crystallization process was then repeated yielding 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (15.385 g, 38 mmole) as white crystal at a yield of 74%.
  • 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine (20 g, 86.6 mmole) was added to 430 mL of DMF. Some of the solid material did not dissolve. To this solution was added 43 mL of a 10% NaOH (w/v) solution. With vigorous stirring, the un-dissolved material went into solution. The resulting solution was divided into 30 equal portions of 16.3 mL, 3 mmole of 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine so as to fit into a microwave reaction vessel.
  • the resulting crude material was dissolved in CH 2 Cl 2 , purified using a 330 g SiO 2 column (Redisep (Isco) 0% to 0%/5 min to 10%/B/30 nin to 20%/5 min), and the resulting material was re-crystallized from ethanol/H 2 O.
  • the three batches yielded 14 g, 33.5 mmole of 5-(4-(trifluoromethoxy)benzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine.
  • 2,4-difluorophenylboronic acid (196 mg, 1.24 mmole) was added to a solution of 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (460 mg, 1.03 mmole) in DMF (10 mL).
  • Na 2 CO 3 was dissolved in H 2 O, added to the DMF solution and stirred Pd(PPh3)4 was then added to the DMF reaction mixture.
  • the reaction mixture was heated in a microwave at 200° C. for 2 minutes.
  • 2,4-(bis-trifluoromethyl)benzaldoxime (9.75 g, 0.038 mol) was suspended in CH 2 Cl 2 (45 mL, 0.85 M) and cooled to 4° C.
  • Propargyl chloride (2.72 mL, 0.038 mol) was added to the reaction solution followed by dropwise addition of NaOCl (10-13% free chlorine, 37.6 mL, 0.061 mol).
  • the reaction mixture was stirred at 4° C. for 15 min then heated to reflux for 3 h. After cooling to room temperature, the reaction was partitioned between CH 2 Cl 2 and H 2 O. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, the crude product chioromethylisoxazole was purified by column chromatography on silica (10% CH 2 Cl 2 /hexanes)(6.5 g ,0.020 mol).
  • the solid material was recrystallized from EtoAc/hexanes to obtain 5-((3-(2-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine in 69% yield.
  • Example 7B Either salt of Example 7B was mixed 1:1 by weight in dry pregelatized starch. 100 mg of the mixture was loaded into a hard gel capsule.
  • the scaffold in this case 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine
  • the total amount of 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine was dissolved in enough DMF to give 500 ul/reaction.
  • To each solution was added 60 ⁇ L of 10%(w/v)NaOH/H 2 O.
  • the alkylating agents were dissolved in DMF at a concentration 480 ⁇ mole/mL and 250 ⁇ L of these solutions were added to the respective reaction.
  • Each reaction was then heated to 110° C. for 1 min using microwave irradiation.
  • the aryl boronic acid (1.2 eq.) was added to a solution of 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (1 eq.) in DMF.
  • Na 2 CO 3 (2 eq) was dissolved in H 2 O, added to the DMF solution and stirred.
  • Pd(PPh3)4 was then added to the DMF reaction mixture.
  • the reaction mixture was heated in a microwave at 200° C. for 2 minutes.
  • the reaction mixture was applied to a 1 g solid phase extraction cartridge (C-18) and the column was washed with 3 ⁇ 2 mL of methanol.
  • the eluents were filtered through a 0.45 um filter and then concentrated to dryness.
  • the resulting material was redissolved in DMF, and purified by reverse phase HPLC/MS.
  • Oxime was suspended in CH 2 Cl 2 and cooled to 4° C. Propargyl chloride (1 equiv.) was added to the reaction solution followed by dropwise addition of NaOCl (10-13% free chlorine, 1 equiv.). The reaction mixture was stirred at 4° C. for 15 min then heated to reflux for 3 h. After cooling to room temperature, the reaction was partitioned between CH 2 Cl 2 and H 2 O. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, the crude product was purified by trituration (hexanes ) or by column chromatography on silica (10% CH 2 Cl 2 /hexanes).
  • the aryl bromide (1.2 eq.) was added to a solution of 4-((2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridin-5-yl)methyl)phenylboronic acid (1 eq.) in DMF.
  • Na 2 CO 3 (2 eq) was dissolved in H 2 O, added to the DMF solution and stirred.
  • Pd(PPh 3 ) 4 (5 mole %) was then added to the DMF reaction mixture.
  • the reaction mixture was heated in a microwave at 200° C. for 2 minutes.
  • the reaction mixture was applied to a 1 g solid phase extraction cartridge (C-18) and the column was washed with 3 ⁇ 2 mL of methanol.
  • the eluents were filtered through a 0.45 um filter and then concentrated to dryness.
  • the resulting material was redissolved in DMF, and purified by reverse phase HPLC/MS.
  • the appropriately substituted 4′-[2-(2,3-Difluoro-phenyl)-imidazo[4,5-c]pyridin-5-ylmethyl]-biphenyl4-ol (5) scaffold was prepared by first treating 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine) (1) with 1-bromomethyl-4-iodobenzene (2) in DMF using aqueous sodium hydroxide as base.
  • Example 9 95 387.340 388.340 A
  • Example 10 90 395.440 396.440 A
  • Example 11 90 413.431 414.431 A
  • Example 12 92 404.451 405.541 A
  • Example 13 95 407.451 408.451 A
  • Example 14 85 405.479 406.479 A
  • Example 15 90 389.331 390.331 A
  • Example 16 90 431.418 432.418 A
  • Example 17 93 404.834 405.834 A
  • Example 18 90 370.389 371.389 A
  • Example 19 95 389.331 390.331 A
  • Example 20 95 389.331 390.331 A
  • Example 21 95 389.331 390.331 A
  • Example 22 97 355.777 356.777 A
  • Example 23 90 407.451 408.451
  • Example 24 90 461.134 462.134 A
  • Example 25 90 401.404 402.404 A
  • Example 26 95 371.377 372.377 A
  • Example 27 95 439.375 440.375 A
  • Example 28 90 405.822
  • MDBK Madin-Darbey Bovine Kidney cells were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with BVDV-free 5% fetal calf serum (DMEME-FCS) at 37° C. in a humidified, 5% CO 2 atmosphere.
  • BVDV-1 strain PE5175 was used to assess the antiviral activity in MDBK cells.
  • the 50% effective concentration (EC 50 ) value was defined as the concentration of compound that protects 50% of the cell monolayer from virus-induced cytopathic effect.
  • Huh-5-2 cells [a cell line with a persistent HCV replicon I3891uc-ubi-neo/NS3-3′/5.1; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B HCV polyprotein] was cultured in RPMI medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine (Life Technologies), 1 ⁇ non-essential amino acids (Life Technologies); 100 IU/mL penicillin and 100 ug/ml streptomycin and 250 ug/mL G418 (Geneticin, Life Technologies).
  • Cells were seeded at a density of 7000 cells per well in 96 well View PlateTM (Packard) in medium containing the same components as described above, except for G418. Cells were allowed to adhere and proliferate for 24 hr. At that time, culture medium was removed and serial dilutions of the test compounds were added in culture medium lacking G418. Interferon alfa 2a (500 IU) was included as a positive control. Plates were further incubated at 37° C. and 5% CO 2 for 72 hours. Replication of the HCV replicon in Huh-5 cells results in luciferase activity in the cells.
  • Luciferase activity is measured by adding 50 ⁇ L of 1 ⁇ Glo-lysis buffer (Promega) for 15 minutes followed by 50 ⁇ L of the Steady-Glo Luciferase assay reagent (Promega). Luciferase activity is measured with a luminometer and the signal in each individual well is expressed as a percentage of the untreated cultures. Parallel cultures of Huh-5-2 cells, seeded at a density of 7000 cells/well of classical 96-well cell culture plates (Becton-Dickinson) are treated in a similar fashion except that no Glo-lysis buffer or Steady-Glo Luciferase reagent is added. Instead the density of the culture is measured by means of the MTS method (Promega).
  • Replicon cells were plated at 7.5 ⁇ 10 3 cells per well in a 96-well plate plates at 37° C. and 5% CO 2 in Dulbecco's modified essential medium containing 10% fetal calf serum, 1% nonessential amino acids and 1 mg/ml Geneticin. After allowing 24 h for cell attachment, different dilutions of compound were added to the cultures. Plates were incubated for 5 days, at which time RNA was extracted using the Qiamp Rneazyi Kit (Qiagen, Hilden, Germany).
  • a 50 ⁇ L PCR reaction contained TaqMan EZ buffer (50 mmol/L Bicine, 115 mmol/L potassium acetate, 0.01 mmol/L EDTA, 60 mmol/L 6-carboxy-X-rhodamine, and 8% glycerol, pH 8.2; Perkin Elmer Corp./Applied Biosystems), 300 ⁇ mol/L deoxyadenosine triphosphate, 300 ⁇ mol/L deoxyguanosine triphosphate, 300 ⁇ mol/L deoxycytidine triphosphate, 600 ⁇ mol/L deoxyuridine triphosphate, 200 ⁇ mol/L forward primer [5′-ccg gcT Acc Tgc ccA TTc], 200 ⁇ mol/L reverse primer [ccA GaT cAT ccT gAT cgA cAA G], 100 ⁇ mol/L TaqMan probe [6-FAM-AcA Tcg cAT cgA g Agc
  • Ct-value is defined as the number of PCR cycles for which the signal exceeds the baseline, which defines a positive value. The sample was considered to be positive if the Ct-value was ⁇ 50. Results are expressed as genomic equivalents (GE).
  • the effect of the drugs on exponentially growing MDBK cells was assessed as follows. Cells were seeded at a density of 5000 cell/well in 96 well plates in MEM medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine (Life Technologies) and bicarbonate (Life Technologies). Cells were cultured for 24 hr after which serial dilutions of the test compounds were added. Cultures were then again further incubated for 3 days after which the effect on cell growth was quantified by means of the MTS method (Promega). The concentration that results in 50% inhibition of cell growth is defined as the 50% cytostatic concentration (CC 50 )
  • the compounds of Examples 2, 3A, 4 and 5 were found to have an EC50 in Replicon assay 2 of, respectively in micromoles, 0.01, 0.02, 0.01 and 0.0039, and to have a CC50 in the CC50 assay protocol of, respectively in micromoles, 26, 34, 19 and 10.8 (replicate 13.4).
  • Substantially all of the compounds in Table 1 demonstrated activity of at least 1 micromolar in an anti-HCV/Replicon assay system. In addition, a number of the compounds also exhibited anti-BVDV activity.

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Abstract

The present invention relates to pharmaceutical compositions for the treatment or prevention of viral infections comprising as an active principle at least one imidazo[4,5-c]pyridine prodrug having the general Formula (A) wherein the substituents are described in the specification. The invention also relates to processes for the preparation and screening of compounds according to the invention having above mentioned general Formula and their use in the treatment or prophylaxis of viral infections.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 10/583,814, filed Jun. 22, 2006, which is the U.S. National Stage of International Application No. PCT/US2004/043112, filed Dec. 21, 2004, which, in turn, claims the benefit of U.S. Provisional Patent Application Ser. Nos. 60/532,292 (filed Dec. 22, 2003), 60/533,963 (filed Jan. 2, 2004), 60/591,069 (filed Jul. 26, 2004), 60/591,024 (filed Jul. 26, 2004), 60/590,989 (filed Jul. 26, 2004), and 60/590,990 (filed Jul. 26, 2004); the disclosures of each are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to a series of novel imidazo[4,5-c]pyridine compounds, processes for their preparation, their use to treat or prevent viral infections and their use to manufacture a medicine to treat or prevent viral infections, particularly infections with viruses belonging to the family of the Flaviviridae and Picomavitidae and more preferably infections with hepatitis-C-virus (HCV).
BACKGROUND OF THE INVENTION
The family of the Flaviviridae consists of 3 genera, the pestiviruses, the flaviviruses and the hepaciviruses and also contains the hepatitis G virus (HGV/GBV-C) that has not yet been assigned to a genus. Pestiviruses such as the Classical Swine Fever Virus (CSFV), the Bovine Viral Diarrhea Virus (BVDV) and the Border Disease Virus (BDV) cause infections of domestic livestock (respectively pigs, cattle and sheep) and are responsible for significant economic losses world-wide. BVDV, the prototypic representative of the pestivirus genus is ubiquitous and causes a range of clinical manifestations, including abortion, teratogenesis, respiratory problems, chronic wasting disease, immune system dysfunction, and predisposition to secondary viral and bacterial infections and may also cause acute fatal disease. Fetuses of cattle can be infected persistently with BVDV, these animals remain viremic throughout life and serve as a continuous source for virus spread in herds.
Vaccines are used in some countries with varying degrees of success to control pestivirus disease. In other countries, animal culling and slaughter are used to contain pestivirus disease outbreaks.
The World Health Organization estimates that world-wide 170 million people (3% of the world's population) are chronically infected with HCV. These chronic carriers are at risk of developing cirrhosis and/or liver cancer. In studies with a 10 to 20 year follow-up, cirrhosis developed in 20-30% of the patients, 1 to 5% of who may develop liver cancer during the next then years. The only treatment option available today is the use of interferon α-2 (or its pegylated from) either alone or combined with ribavirin. However, sustained response is only observed in about 40% of the patients and treatment is associated with serious adverse effects. There is thus an urgent need for potent and selective inhibitors of the replication of the HCV in order to treat infections with HCV. Furthermore, the study of specific inhibitors of HCV replication has been hampered by the fact that it is not possible to propagate HCV (efficiently) in cell culture. Since HCV and pestiviruses belong to the same virus family and share many similarities (organization of the genome, analogous gene products and replication cycle), pestiviruses have been adopted as a model and surrogate for HCV. For example, BVDV is closely related to hepatitis C virus (HCV) and used as a surrogate virus in drug development for HCV infection.
The compound 3-[((2-dipropylamino)ethyl)thio]-5H-1,2,4-triazino[5,6-b]indole has been reported to selectively inhibit the replication of BVDV and other pestiviruses (Baginuli S G et al., Proc. Natl. Acad. Sci. U.S.A. 2000 Jul 5; 97(14):7981-6). Currently, there is no treatment strategy available for controlling infections caused by pestiviruses.
Coxsackie viruses belong to the group of the enterovinuses, family of the Picomaviridae. They cause a heterogeneous group of infections including herpangina, aseptic meningitis, a common-cold-like syndrome, a non-paralytic poliomyelitis-like syndrome, epidemic pleurodynia (an acute, febrile, infectious disease generally occurring in epidemics), hand-foot-mouth syndrome, pediatric and adult pancreatitis and serious myocarditis.
Currently only pleconaril (3-13,5-dimethyl-4-[[3-methyl-5-isoxazolyl)propyl]phenyl]-5-(trifluoromethyl-1,2,4-oxadiazole)) and enviroxime (2-amino-1-(isopropylsulfonyl)-6-benzimidazole phenyl ketone oxime) have been studied clinically for the treatment of infections with enteroviruses. Pleconaril is a so called “capsid function-inhibitor”; enviroxime prevents the formation of the RNA replicative intermediate. Enviroxime resulted in only modest clinical and virological benefit in some studies and no benefits in others. Clinical response with pleconaril has been observed in some studies, but the compound has not been approved by the Food and Drug Administration (hearing of Mar. 18, 2002).
Relevant disclosures include U.S. Pat. Nos. 4,914,108; 4,988,707; 4,990,518; 5,137,896; 5,208,242; 5,227,384; 5,302,601; 5,374,638; 5,405,964; 5,438,063; 5,486,525; 6,479,508; and U.S. Patent Publication No. US2003/0108862 A1, Canadian Patent No. 2423800 A1, German Patent Nos. 4211474 A1, 4236026, 4309969, 4318813, European Patent Nos. EP 0 138 552 A2, EP 0 706 795 A2, EP 1 132 381 A1, Great Britain Patent No. 2158440 A, PCT Patent Publication Nos. WO 00/20416, WO 00/39127, WO 00/40583, WO 03/007945 A1, WO 03/010140 A2, WO 03/010141 A2, WO 93/02080, WO 93/14072, WO 96/11192, WO 96/12703, WO 99/27929, Akamatsu, et al., New Efficient Route for Solid-Phase Synthesis of Benzimidazole Derivatives”, 4:475-483, J. COMB. CHEM, 2002, Cleve et al., “Derivate des Imidazo[4.5-b]- und Imidazo[4.5-c]pyridins”, 747:158-171, JUSTUS LIEBIGS ANNALEN DER CHEMICA, 1971, Kiyana, et al., “Synthesis and Evaluation of Novel Nonpeptide Angiotensin II Receptor Antagonists: Imidazo[4,5-c]pyridine Derivatives with an Aromatic Substituent”, 43(3):450-60, CHEM PHARM BULL, 1995, Mederski et al., “Synthesis and Structural Assignment of Some N-substituted Imidazopyridine Derivatives”, 48(48): 10549-58, TETRAHEDRON, 1992, Yutilov et al., 23(1):56-9, KHIMIKO-FARMTSEVTICHESKII ZHURNAL, 1989. The disclosures of all citations set forth herein are expressly incorporated by reference to the extent such disclosures are relevant to the contents herein.
A need exists for compounds having antiviral and other desirable properties, such as bioavailability, efficacy, nontoxicity, optima clearance, potency and the like. In particular, a need exists for compounds having selective activity against viruses belonging to the family of Flaviviridae including hepatitis C virus, and against viruses belonging to the family of Picornaviridae. These and other objects of this invention will be apparent to one skilled in the art from consideration of this specification as a whole.
SUMMARY OF THE INVENTION
An embodiment of the present invention provides compounds having the general formula (A),
Figure US08329727-20121211-C00001
wherein:
the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds;
R1 is selected from hydrogen, aryl, heterocyclic, C1-C10 alkoxy, C1-C10 thioalkyl, 1-C10 alkyl-amino, C1-C10 dialkyl-amino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R6;
Y is selected from single bond, O, S(O)m, NR11, or C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, wherein each may optionally include 1 to 3 heteroatoms selected from O, S or N;
R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocyclic, provided that when one of R25 or R26 is present, then either R2 or R4 is selected from (═O), (═S), and ═NR27;
X is selected from C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or N, provided any such heteroatom is not adjacent to the N in the ring;
m is any integer from 0 to 2;
R3 is selected from aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl-N(R10)—, or heterocyclic, where each said substituent may be optionally substituted with at least one R17, provided that for cycloalkenyl the double bond is not adjacent to a nitrogen, and provided R3-M-Q is not biphenyl;
R5 is selected from hydrogen; C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocyclic;
R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, C1-18 haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, heterocyclic, C1-18 hydroxyalkyl, where each may be optionally substituted with at least 1 R19;
R7 and R8 are independently selected from hydrogen, C1-18 alkyl, C1-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocyclic, —C(═O)R12; —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or where R7 and R8 together with the nitrogen form a heterocyclic;
R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —N15R16, aryl, an amino acid residue linked through an amino group of the amino acid, CH2OCHO(═O)R9a, or CH2OC(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
R10 and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocyclic, or an amino acid residue;
R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
R13 and R14 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, —C(═S)R12, or an amino acid residue;
R15 and R16 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
R17 is independently M-Q- wherein M is a ring optionally substituted with 1 or more R19, and Q is a bond or a liking group connecting M to R3 having 1 to 10 atoms and optionally substituted with 1 or more R19;
R19 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR20R21, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocyclic, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18alkyl)oxy, arylthio, aryl(C1-18)alkylthio or aryl(C1-18)alkyl, where each may be optionally substituted with 1 or more ═O, NR20R21, CN, C1-18 alkoxy, heterocyclic, C1-18 haloalkyl, heterocyclic alkyl, heterocyclic connected to R17 by alkyl, alkoxyalkoxy or halogen;
R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, or —C(═S)R12;
R22 is selected from hydrogen, —OH, C1-18 alkyl, C2-18 alkylenyl, C1-18 alkoxy, —NR23R24, aryl, C3-10 cycloalkyl, and C4-10 cycloalkenyl;
R23 and R24 are independently selected from hydrogen, C1-18 alkyl, or a heterocyclic formed by taking C2-3 alkyl together with N of R22, which heterocyclic is optionally substituted with OH or aryl, or an amino acid residue linked through a carboxyl group of the amino acid;
R25 and R26 are not present, or are independently selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, aryl, heterocyclic, where each is optionally independently substituted with 1 to 4 of C1-6 alkyl, C1-6 alkoxy, halo, CH2OH, benzyloxy, and OH; and
R27 is selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, (C3-10 cycloalkyl)-C1-6 alkyl, aryl, and aryl C1-18 alkyl, and
salts, tautomers, isomers and solvates thereof.
Another embodiment of the present invention provides compounds having the general formula (A),
Figure US08329727-20121211-C00002
wherein:
the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds;
R1 is selected from hydrogen, aryl, heterocyclic, C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkyl-amino, C1-C10 dialkyl-amino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R6;
Y is selected from single bond, O, S(O)m, NR11, or C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, wherein each may optionally include 1 to 3 heteroatoms selected from O, S or N;
R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocyclic, provided that when one of R25 or R26 is present, then either R2 or R4 is selected from (═O), (═S), and ═NR27;
X is selected from C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or N, provided any such heteroatom is not adjacent to the N in the ring;
m is any integer from 0 to 2;
R3 is a heterocycle optionally substituted with at least one R17 provided, however, that R3 optionally substituted with at least one R17 is not pyridinyl or 5-chlorothienyl, provided that R3-MQ is not biphenyl;
R5 is selected from hydrogen; C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocyclic;
R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, heterocyclic, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, C1-18 haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, C1-18 hydroxyalkyl, where each may be optionally substituted with at least 1 R19;
R7 and R8 are independently selected from hydrogen, C1-18 alkyl, C1-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocyclic, —C(═O)R12; —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or where R7 and R8 together with the nitrogen form a heterocyclic;
R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, aryl, an amino acid residue linked through an amino group of the amino acid, CH2OCH(═O)R9a, or CH2OC(═O)R9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
R10 and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocyclic, or an amino acid residue;
R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
R13 and R14 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, —C(═S)R12, or an amino acid residue;
R15 and R16 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
R17 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halogenated alkyl, C2-18 halogenated alkenyl, C2-18 halogenated alkynyl, C1-18 halogenated alkoxy, C1-18 halogenated alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, CO2H, CO2R18, NO2, NR7R8, haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocyclic, C1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, or C1-18 hydroxyalkyl is optionally substituted with 1 or more R19;
R19 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR20R21, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6alkyl), aryl, heterocyclic, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18 alkyl)oxy, arylthio, aryl(C1-18)alkylthio or aryl(C1-18)alkyl, where each may be optionally substituted with 1 or more ═O, NR20R21, CN, C1-18 alkoxy, heterocyclic, C1-18 haloalkyl, heterocyclic alkyl, heterocyclic connected to R17 by alkyl, alkoxyalkoxy or halogen;
R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, carboxylester-substituted heterocyclic or —C(═S)R12;
R22 is selected from hydrogen, —OH, C1-18 alkyl, C2-18 alkenyl, C1-18 alkoxy, —NR23R24, aryl, C3-10 cycloalkyl, and C4-10 cycloalkenyl;
R23 and R24 are independently selected from hydrogen, C1-18 alkyl, or a heterocyclic formed by taking C2-3 alkyl together with N of R22, which heterocyclic is optionally substituted with OH or aryl, or an amino acid residue linked through a carboxyl group of the amino acid;
R25 and R26 are not present or are independently selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, aryl, heterocyclic, where each is optionally independently substituted with 1 to 4 of C1-6 alkyl, C1-6 alkoxy, halo, CH2OH, benzyloxy, and OH; and
R27 is selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, (C3-10 cycloalkyl)-C1-6 alkyl, aryl, and aryl C1-18 alkyl, and
the salts, tautomers, isomers and solvates thereof.
An embodiment of the present invention provides compounds having the general formula (A),
Figure US08329727-20121211-C00003
wherein:
the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds;
R1 is selected from hydrogen, aryl, heterocyclic, C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkyl-amino, C1-C10 dialkyl-amino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each are optionally substituted with 1 or more R6;
Y is selected from single bond, O, S(O)m, NR11, or C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene, wherein each may optionally include 1 to 3 heteroatoms selected from O, S or N;
R2 and R4 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocyclic, provided that when one of R25 or R26 is present, then either R2 or R4 is selected from (═O), (═S), and ═NR27;
X is selected from C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene, where each may include one or more heteroatoms selected from O, S, or N, provided any such heteroatom is not adjacent to the N in the ring;
m is any integer from 0 to 2;
R3 is a heterocycle optionally substituted with at least one R17, provided R3-M-Q is not biphenyl;
R5 is selected from hydrogen; C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, or heterocyclic;
R6 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, cyanoalkyl, —CO2R18, NO2, —NR7R8, C1-18 haloalkyl, C(═O)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, heterocyclic, C1-18 hydroxyalkyl, where each maybe optionally substituted with at least 1 R19;
R7 and R8 are independently selected from hydrogen, C1-18 alkyl, C1-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocyclic, —C(═O)R12; —C(═S)R12, an amino acid residue linked through a carboxyl group thereof, or where R7 and R8 together with the nitrogen form a heterocyclic;
R9 and R18 are independently selected from hydrogen, OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, aryl, an amino acid residue linked through an amino group of the amino acid, CH2OCH(═O)R9a, or CH2OC(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
R10 and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═)R12heterocyclic, or an amino acid residue;
R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
R13 and R14 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, —C(═S)R12, or an amino acid residue;
R15 and R16 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, or an amino acid residue;
R17 is M-Q-, wherein M is a C3-10 cycloalkyl optionally substituted with 1 or more R19, and Q is a bond, or C1-10 alkyl optionally substituted with 1 or more R19;
R19 is selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═O)OR18, —OalkenylC(═O)OR18, —OalkylC(═O)NR20R21, —OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocyclic, C1-18alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18 alkyl)oxy, arylthio, aryl(C1-18)alkylthio or aryl(C1-18)alkyl, where each may be optionally substituted with 1 or more ═O, NR20R21, CN, C1-18 alkoxy, heterocyclic, C1-18 haloalkyl, heterocyclic alkyl, heterocyclic connected to R17 by alkyl, alkoxyalkoxy or halogen;
R20 and R21 are independently selected from hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, or —C(═S)R12;
R22 is selected from hydrogen, —OH, C1-18 alkyl, C2-18 alkenyl, C1-18 alkoxy, —NR23R24, aryl, C3-10 cycloalkyl, and C4-10 cycloalkenyl;
R23 and R24 are independently selected from hydrogen, C1-18 alkyl, or a heterocyclic formed by taking C2-3 alkyl together with N of R22, which heterocyclic is optionally substituted with OH or aryl, or an amino acid residue linked through a carboxyl group of the amino acid;
R25 and R26 are not present, or are independently selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, aryl, heterocyclic, where each is optionally independently substituted with 1 to 4 of C1-6 alkyl, C1-6 alkoxy, halo, CH2OH, benzyloxy, and OH; and
R27 is selected from hydrogen, C1-18 alkyl, C3-10 cycloalkyl, (C3-10 cycloalkyl)-C1-6 alkyl, aryl, and aryl C1-18 alkyl, and
the salts, tautomers, isomers and solvates thereof.
Yet another embodiment of the present invention provides compounds having the formula (B),
Figure US08329727-20121211-C00004
wherein:
the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3, optionally 4 double bonds; and R1, R2, R3, R4, R5, R25, R26, X and Y are as disclosed above.
An embodiment of the present invention provides compounds of the formula (B) wherein Y is a single bond, and R1 is aryl.
Another embodiment of the present invention provides compounds of formula (B) wherein X is C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene.
Another embodiment of the present invention provides compounds of formula (B) wherein R3 is heterocyclic.
Another embodiment of the present invention provides compounds of formula (B) wherein R3 is heterocyclic substituted with R17 where Q is a bond and M is aryl.
Another embodiment of the present invention provides compounds of formula (B) wherein Y is a single bond, and R1 is phenyl.
Another embodiment of the present invention provides compounds of formula (B) wherein R3 is isoxazole substituted with R17 where Q is a bond and M is aryl.
Another embodiment of the present invention provides compounds of formula (B) wherein R3 is isoxazole substituted with R17 where Q is a bond and M is phenyl.
Yet another embodiment of the present invention provides compounds having the formula (C),
Figure US08329727-20121211-C00005
wherein R1, R2, R3, R4, R5, R25, R26, X and Y are as disclosed above.
An embodiment of the present invention provides compounds of the formula (C) wherein Y is a single bond, and R1 is aryl.
Another embodiment of the present invention provides compounds of formula (C) wherein X is C1-C10 alkylene, C2-10 alkenylene or C2-10 alkynylene.
Another embodiment of the present invention provides compounds of formula (C) wherein R3 is heterocylic.
Another embodiment of the present invention provides compounds of formula (C) wherein R3 is heterocyclic substituted with R17 where Q is a bond and M is aryl.
Another embodiment of the present invention provides compounds of formula (C) wherein Y is a single bond, and R1 is phenyl.
Another embodiment of the present invention provides compounds of formula (C) wherein R3 is isoxazole substituted with R17 where Q is a bond and M is aryl.
Another embodiment of the present invention provides compounds of formula (C) wherein R3 is isoxazole substituted with R17 where Q is a bond and M is phenyl.
The compounds of formula (A) are optionally combined with pharmacologically acceptable excipients.
The compounds of formula (A) are administered in therapeutically effective amounts to subjects (humans or animals) in need of antiviral therapy, in particular for inhibiting the infection, growth or replication of Flaviviridae and Picornaviridae, especially BVDV, HCV and Coxsackie virus.
The invention further relates to a method of screening antiviral compounds which comprises providing a compound of formula (A) and determining the anti-viral activity of said compound.
Also within the scope of the invention is a metabolite of the compounds of formula (A) made by the process of administering a compound of formula (A) to a subject and recovering the metabolite from the subject.
The invention also comprises a method for structure-activity determination of analogues of formula (A) compounds
Figure US08329727-20121211-C00006
wherein the substituents are defined in WO 2004/005286, comprising
    • (A) preparing a compound of formula (A) in which at least one substituent is not disclosed by WO 2004/005286; and
    • (B) determining the anti-HCV activity of the compound of step (a).
DETAILED DESCRIPTION OF THE INVENTION
“Alkyl” means saturated hydrocarbon moiety where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions. The acyclic portion may contain 1 to 3 carbon atoms, and each ring may contain 3 to 6 carbon atoms (for example, 3-methylcyclohexyl). Within this definition, the term “cycloalkyl” refers to the saturated hydrocarbon moieties that are cyclic. Examples of “alkyl” include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl(i-Bu), 2-butyl (s-Bu) 2-methyl-2-propyl (t-Bu), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-methyl-2-butyl, 3,3-dimethyl-2-butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, cyclooctyl and the like, or a C7-10 polycyclic saturated hydrocarbon radical having from 7 to 10 carbon atoms such as, for instance, norbornyl, fenchyl, trimethyltricycloheptyl or adamantyl.
“Alkenyl” means a hydrocarbon moiety with at least one site of double bond unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions. The acyclic portion may contain 1 to 3 carbon atoms, and each cyclic portion may contain 3 to 6 carbon atoms. A site of double bond unsaturation maybe in a acyclic portion, a cyclic portion. In the instance of a moiety having a combination of acyclic and cyclic portions, there may be a site of double bond unsaturation in each of the portions. Within this definition, the term “cycloalkenyl” refers to the double bond unsaturated hydrocarbon moieties that are cyclic. Examples the term “alkenyl” include, but are not limited to, ethylene or vinyl (—CH═CH2), allyl (—CH2CH═CH2), cyclopentenyl (—C5H7), 5-hexenyl (—CH2CH2CH2CH2CH═CH2), 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl. The double bond optionally is in the cis or trans configuration.
“Alkynyl” means a hydrocarbon moiety with a least one site of triple bond unsaturation where the moiety may be acyclic, cyclic or a combination of acyclic and cyclic portions. The acyclic portion may contain contain 1 to 3 carbon atoms, and each cyclic portion may contain 7 or more carbon atoms. Within this definition, the term “cycloalkenyl” refers to triple bond unsaturated hydrocarbon moieties that are cyclic. Examples of the term “alkynyl” include, but are not limited to, —C≡CH, —CH2C≡CH, —CH2C≡C-cyclohexyl, or —CH2-cycloheptynyl.
The suffix “-ene” used in connection with alkyl, alkenyl and alkynyl groups refers to such groups with at least 2 sites of substitution. Such polyvalent hydrocarbon radicals include, but are not limited to, methylene (—CH2—) 1,2-ethylene (—CH2CH2—), 1,3-propylene (—CH2CH2CH2—), 1,4-butylene (—CH2CH2CH2CH2—), 1,2-ethylene (—CH═CH—), —C□C—, propargyl (—CH2C□C—), and 4-pentynyl (—CH2CH2CH2C□CH—).
“Aryl” means an aromatic hydrocarbon containing 1 or more rings, generally 1, 2 or 3, with 4 to 6 carbon atoms in each, ordinarily 5 or 6 carbon atoms.
“Arylalkyl,” “arylalkenyl” and “arylalkynyl” means an alkyl, alkenyl or alkynyl radical, respectively, in which one of the hydrogen atoms, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylehian-1-yl and the like.
As noted, carbocycles optionally are found as single rings or multiple ring systems. Ordinarily the hydrocarbons of the compounds of formula (A) are single rings. Monocyclic carbocycles generally have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles typically have 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
If the number of carbon atoms is unspecified for a hydrocarbon, typically the number of carbon atoms will range from 1 to 18, except that the number of carbons typically will range from 2 to 18 for unsaturated hydrocarbons and from 6 to 10 for aryl.
“Heterocyclic” or “heterocycle” means any 4, 5, 6, 7, 8 or 9 membered single or fused ring system containing one or more heteroatoms selected from the group consisting of O, N or S. Heterocycles optionally are entirely aromatic, entirely saturated, or contain 1 or more intra-ring sites of unsaturation, typically double bonds. Multiple heterocyclic rings (one or more of which contains a heteroatom) are bridged or spiro. Generally, the heterocyclic rings will be aromatic, and usually they are single rings. Examples of heterocycles include oxazacyloalkyl, morpholinyl, dioxacycloalkyl, thiacycloalkenyl, pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, furanyl, thienyl, pyrrolyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl, tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isothiazoledinyl, isoxazolyl, oxazolinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyruiidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, benzothienyl, benzothiazolyl and isatinoyl. Other suitable heterocycles are exemplified in Rigaudy et al., Nomenclature of Organic Chemistry, Sections A-H (1979) at pp. 53-76 and Fletcher et al., Nomenclature of Organic Compounds, Adv. Chem. Ser. 126 (1974) at pp 49-64.
The location on the heterocycle which provides the point of attachment(s) to the rest of the compound of this invention is not critical, but those skilled in the art will recognize substitution sites that are optimal for compound stability and/or ease of synthesis. Carbon bonded heterocycles typically are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrminidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
Nitrogen containing heterocycles are bonded at nitrogen or a carbon, typically a carbon atom. These include, for example, position 1 of aziridine, 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-piperidinyl, 2-pyrroline, 3-pyrroline, 2-imidazoline, 3-imidazoline, 9-carbazole, 4-morpholine, 9-alpha or β-carboline, 2-isoindole, 2-pyrazoline and 3-pyrazoline, and by analogy, azetidine, pyrrole, pyrrolidine piperidine, piperazine, indole, pyrazoline, indoline, imidazole, imidazolidine, 1H-indazole and isoindoline. These and other N-containing heterocycles are well-known to those skilled in the art, and their linkage sites are a matter of discretion.
Sulfur containing heterocycles are bonded through carbon or sulfur. They include oxidized states such as —S(═O)(═O). In general, they are linked in the compounds of formula (A) analogous to N-containing heterocycles.
“Alkoxy”, “cycloalkoxy”, “aryloxy”, “arylalkyloxy”, “oxy heterocycle”, “thioalkyl”, “thiocycloalkyl”, “arylthio”, and “arylalkylthio” means substituents wherein an alkyl, cycloalkyl, aryl, or arylalkyl, respectively, are attached to an oxygen atom or a sulfur atom through a single bond, such as but not limited to methoxy, ethoxy, propoxy, butoxy, thioethyl, thiomethyl, phenyloxy, benzyloxy, mercaptobenzyl and the like.
“Halogen” means any atom selected from the group consisting of fluorine, chlorine, bromine and iodine.
Any substituent designation that is found in more than one site in a compound of this invention shall be independently selected.
When a group is stated to be substituted with “one or more” of another group, this typically means 1 to 3 substituents, ordinarily 1, 2 or 3 substitutents.
Those of skill in the art will also recognize that the compounds of the invention may exist in many different protonation states, depending on, among other things, the pH of their environment. While the structural formulae provided herein depict the compounds in only one of several possible protonation states, it will be understood that these structures are illustrative only, and that the invention is not limited to any particular protonation state—any and all protonated forms of the compounds are intended to fall within the scope of the invention.
Amino Acids
“Amino-acid” refers to a radical derived from a molecule having the chemical formula H2N—CHR28—COOH, wherein R28 is a side group of a naturally-occurring or known synthetic amino-acid. The amino acids optionally are substituted with hydrocarbon typically of 1 to 8 carbons at one or more carboxyl or amino groups, whether those groups are on the side chain or are free after linking the amino acid to the remainder of the compound of this invention.
Optionally the amino acid residue is a hydrophobic residue such as mono- or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. Optionally, the residue does not contain a sulhydryl or guanidino substituent.
Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included.
Generally, only oxie of any site in the parental molecule is substituted with an amino acid, although it is within scope of this invention to introduce amino acids at more than one permitted site. In general, the α-amino or α-carboxyl group of the amino acid are bonded to the remainder of the molecule, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates).
The amino acid esters optionally are hydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions. Optionally, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
R28 usually is C1-C6 alkyl or C1-C6 alkyl substituted with amino, carboxyl, amide, carboxyl (as well as esters, as noted above), hydroxyl, C6-C7 aryl, ganidinyl, imidazolyl, indolyl, sulhydryl, sulfoxide, and/or alkylphosphate. R28 also is nitrogen to form a proline residue taken together with the amino acid α. However, R28 is generally the side group of the naturally-occurring amino acid disclosed above, for example H, —CH3, —CH(CH3)2, —CH2—CH(CH3)2, —CHCH3—CH2—CH3, —CH2—C6H5, —CH2CH2—S—CH3, —CH2OH, —CH(OH)—CH3, —CH2—SH, —CH2—C6H4OH, —CH2—CO—NH2, —CH2—CH2—CO—NH2, —CH2—COOH, —CH2—CH2—COOH, —(CH2)4—NH2 and —(CH2)3—NH—C(NH2)—NH2. R28 also includes 1-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
Exemplary Embodiments
R1 is generally aryl or aromatic heterocyle substituted with 1, 2 or 3 R6 wherein R6 is halogen, C1-18 alkoxy; or C1-18 haloalkyl. Typically, R1 is phenyl substituted with 1, 2 or 3 halogens, usually fluoro.
Y generally is a single bond, O, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene or one of said groups containing 1 to 3, usually 1, heteroatoms selected from O, S or NR11. Examples include —O(CH2)1-5—, —(CH2)1-4—O—(CH2)1-4—, S—(CH2)1-5—, —(CH2)1-4—S—(CH2)1-4—, —NR11—(CH2)1-5—, —(CH2)1-4—NR11—(CH2)1-4 or C3-10 cycloalkylidene. Typically, Y is —OCH2—, —CH2O—, C1-2 alkylene, C2-3 alkenylene, C2-3 alkynylene, O or a bond, but usually a bond.
In general, YR1 is not any one of H, an unsubstituted C3-10 cycloalkyl or C1-C6 alkyl. Typically YR1 is halo or halomethyl-substituted (typically trihalomethyl) phenyl (and usually 1 to 2 substituents in ortho or meta).
X usually is alkylene, alkynylene or alkenylene, typically alkylene, or said hydrocarbons having an intrachain heteroatom, typically O or S. Examples include —CH2—, —CH(CH3)—, —CH2—CH2—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2, —(CH2)2-4—O—(CH2)2-4—, —(CH2)2-4—S—(CH2)2-4—, —(CH2)2-4—NR10—(CH2)2-4—, C3-10 cycloalkylidene, C2-6 alkenylene (such as —CH═CH—CH2—) and C2-6 alkynylene. Usually, X is methylene.
R3 generally is aryl or a heterocycle, typically an aromatic heterocycle. The heterocycle generally will contain 1, 2 or 3 N, S or O atoms in the ring, usually is linked to X through a ring carbon atom and typically contains 4 to 6, usually 5, total ring atoms. The R3 aryl or heterocycle ordinarily is substituted with 1, 2 or 3, usually 1, R17. R3 optionally is not indolyl.
When R3 is substituted with R17 then R17 typically is aryl or a heterocycle further substituted with 1 or more, usually 1, 2 or 3, R19.
R17 is M-Q in some embodiments of the invention. M is a ring. This means any cyclic organic structure, whether carbocyclic or heterocyclic, and whether saturated, unsaturated or aromatic or single or fused ring systems. M is chosen from rings that are structurally stable in biological systems. In general, M is a aryl or aromatic heterocycle where heterocycle is defined above.
Q is a spacer group, and is not critical. Typically it is not cyclic and contains from no to 3 atoms, generally C, O or S, usually C or O.
R17 typically is selected from the group consisting of C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy (optionally an benzyloxy); arylalkylthio (optionally a benzylthio); a heterocycle; C1-18 hydroxyalkyl, but typically is an aryl or a heterocycle, and where each of said aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, or heterocycle is optionally substituted with 1 or more R19. R17 generally is positioned distally to X. Optionally, R17 is not C(O) R18.
R9 and R18 typically are H, OH or alkyl. R18 optionally is not NR15R16.
R5 typically is H.
R6 generally is halogen. Optionally, R6 is not C(O) R18.
R7, R8, R10, R11, R13, R14, R15, R16, R20, R21, R23 and R24 typically are independently H or C1-18 alkyl.
R12 and R22 typically are independently OH or alkyl.
R19 usually is H; C1-18 alkyl; C2-18 alkenyl; C2-18 alkynyl; C1-18 alkoxy; alkenyloxy; alknyloxy; C1-18 alkylthio; C3-10 cycloalkyl; C4-10 cycloalkenyl; C4-10 cycoalkynyl; halogen; OH; CN; cyanoalkyl; NO2; NR20R21; haloalkyl; haloalkyloxy; C(═O)R18; C(═O)OR18; OalkenylC(═O)OR18; —OalkylC(═O)NR20R21; aryl; heterocycle; —OalkylOC(═O)R18; C(═O)N(C1-6 alkyl), N(H)S(O)(O)(C1-6 alkyl); arylalkyloxy; aryloxy; arylalkyloxy; and arylalkyl; each of which is unsubstituted or substituted with 1 or more ═O; NR20R21; CN; alkoxy; heterocycle; haloalkyl- or alkyl-substituted heterocycle; heterocycle linked to R17 by alkyl; alkoxyalkoxy or halogen. R18 as a substituent in here is generally not H. R19 typically is independently halogen, N(R20 R21 ), alkoxy or halo-substituted alkyl or alkoxy.
R25 and R26 usually are not present but if they are then typically they are cyclopentyl or cyclohexyl. If the compound is substituted at R25 or R26, either R2 or R4 is selected from (═O), (═S), and (═NR27), usually ═O.
M typically is an aromatic ring, usually single or two fused rings, and containing 4 to 10 atoms. Usually, M is hydrocarbon, but also optionally comprises 1 to 3 N, O and/or S heteroatoms.
Q usually is a hydrocarbon chain, typically a normal or secondary alkylene, which optionally comprises at least one oxy or thio ester. Generally Q is 1 to 6 atoms, usually 1 to 3. Q typically is not substituted with R19, but if it is then typically it is substituted with one R19. R19 as substituted on Q usually is halogen, nitro or cyano. Substituents optionally are designated with or without bonds. Regardless of bond indications, if a substituent is polyvalent (based on its position in the structure referred to), then any and all possible orientations of the substituent are intended.
Haloalkyl or haloalkyloxy typically are —CF3 or —OCF3.
The present invention provides a compound of Formula (A) of the following the structure,
Figure US08329727-20121211-C00007
having antiviral activity as determined following the procedures taught throughout the Specification, such as in Part B “Methodology For Determination Of Antiviral And Cytostatic Activity” in the Examples Section. Preparation of this compound is taught throughout the Specification, such as in Example 6.
The present invention further provides a compound of Formula (A) of the following structure,
Figure US08329727-20121211-C00008
having antiviral activity as determined following the procedures taught throughout the Specification, such as in Part B “Methodology For Determination Of Antiviral And Cytostatic Activity” in the Examples Section. Preparation of this compound is taught throughout the Specification, such as in Example 8A.
Formula (A) depicts optional single or double bonds. It will be understood that the bonds are present such that the aromatic nature of the nucleus of formula (A) is preserved, i.e., these formulas are intended to embrace all possible tautomers. For example R25 or R26 will be absent if the ring N to which they are bonded as indicated in the formula is linked to a flanking ring carbon atom by a double bond. On the other hand, R25 or R26 may be present when the N atom to which it is bonded as indicated in the formula is linked to its flanking carbon atoms by single bonds only; in this case aromaticity is accommodated by other substituents, e.g. where R2 or R4 is oxo.
The term “prodrug” as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound
Prodrugs
Certain of the compounds herein when substituted with appropriate selected functionalities are capable of acting as prodrugs. These are labile functional groups which separate from an active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). These prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A “prodrug” is thus a covalently modified analog of a therapeutically-active compound. A prodrug moiety of course can be therapeutically active in its own right.
Exemplary prodrug moieties include the hydrolytically sensitive or labile esters (—CO2R′) of carboxylic acids (—CO2H) or other functional groups with an acidic proton which is bound to the imidazo[4,5-c]pyridine compounds of the invention. The R′ group of such hydrolytically sensitive or labile esters may include: (i) acyloxymethyl esters —CH2OC(═O)R9a; and (ii) acyloxymethyl carbonates —CH2OC(═O)OR9a where R9a is C1-C6 alkyl C1-C6 substituted alkyl, C6-C20 aryl or C6-C20 substituted aryl. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the invention. An exemplary acyloxymethyl ester R group is pivaloyloxymethoxy, (POM) —CH2OC(═O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) —CH2OC(═O)OC(CH3)3. Cleavable moieties capable of acting as prodrug functionalities are optionally linked at any tolerant site on the compound of this invention, for example R3 and any of its substituents.
Excluded Compounds
The present invention excludes all compounds expressly disclosed in any prior art reference (to the extent the reference is effective as novelty- or inventive step/obviousness-defeating as the case may be) set forth in this application (as well as any compounds disclosed in any reference patent family member) and and any other compounds over which the claims of this application are not novel or do not posses an inventive step or are obvious under applicable law.
The present invention excludes, as required, compounds according to the general formula (A) where
(a) Any of the substituents X, Y, R1, R2, R3, R4, R5 are a cephalosporin or wherein the substituents X, Y, R1, R2, R3, R4, R5 are an azabicyclo group, more particularly 5-Tia-1-aza-bicyclo[4.2.0]oct-2-en-8-one;
(b) The compound is 5-(2-piperidin-1-yl-ethyl)-2-(4-hydroxyphenyl)-1H-imidazo[4,5-c]pyridin-5-ium bromide (X=ethyl, Y=bond, R1=phenyl substituted in para with OH, R2═H, R3=piperidinyl, and R4, R5═H) ( as disclosed in example 52 of EP 1132381);
(c) The compound is 4-[5-(2-{4-[Bis-(4-fluorophenyl)-methyl]-piperazin-1-yl}-ethyl)-5H-imidazo[4,5-c]pyridin-2-yl]phenol (X=ethyl, Y=bond, R1=phenyl substituted in para with OH, R2═H, R3=heterocycle with 2 N hetero atoms, wherein one N is substituted with an arylalkyl consisting of CH(Phenyl)2, wherein each phenyl carries an F in para) (as disclosed in example 54 of EP 1132381);
(d) The compound is 4-[5-(3-{4-[Bis-(4-fluorophenyl)-methyl]-piperazin-1-yl}-propyl)5H-imidazo[4,5-c]pyridin-2-yl]phenol (X=butyl, Y=bond, R1=phenyl substituted in para with OH, R2═H, R3=heterocycle with 2 N heteroatoms, wherein one N is substituted with an arylalkyl consisting of CH(Phenyl)2, wherein each phenyl carries an F in para) (as disclosed in example 55 of EP 1132381);
(e) The compound is 5-(phenylmethyl)-5H-imidazo[4,5-c]pyridine wherein phenyl is substituted with CONR15R16 and R15 is a branched C3 alkyl and R16 is phenyl (X═—CH2—; Y=bond; R1=hydrogen ; R2═H ; R3=phenyl substituted with 1 C(═O) R18, wherein R18 is NR15R16, with R15 and R16 a branched C6 alkyl ; R4═H) (as disclosed in example 35 of U.S. Pat. No. 5,302,601);
(f) The compound is 6-(5H-imidazo[4,5-c]pyridin-5-yl-methyl)-N-(1methylethyl)-N-phenyl-3-pyridinecarboxamide (X═—CH2—; Y=bond; R1=hydrogen; R2═H, R3=pyridine substituted with 1 R6, wherein. R6=1 C=0 R18, wherein R18 is NR15R16, wherein R15=isopropyl and R16=phenyl) (as disclosed in example 6 of U.S. Pat. No. 4,990,518);
(g) The compound is a compound wherein X═—CH2—; Y=bond; R1=hydrogen; R2═H, R3=5-6 membered heterocycle, in particular a pyridinyl or furanyl, substituted with 1 R17 wherein R17═C(═O)R18, and wherein R18═NR15R16 and R15 and R16 are either a C1-18 alkyl, in particular methyl, ethyl or isopropyl, C2-18 alkenyl, in particular 2-methyl allyl, or a C3-10 cycloalkyl, in particular cyclopentyl or cyclohexyl (as disclosed in U.S. Pat. No. 4,990,518);
(h) The compound is a compound wherein X═—CH2—; Y=bond; R1=hydrogen; R2═H, R3=5-6 membered heterocycle, in particular a pyridinyl or furanyl, substituted with 1 R17 wherein R17═C(═O)R)18, and wherein R18═C3-10 cycloalkyl or C4-10 cycloalkenyl.
(i) The compound is 2,6-bis(1,1,-dimethylethyl)-4-[[2-(5H-imidazo-[4,5-c]pyridin-5-yl)ethyl]thio]-phenol hydrate and/or 2,6-bis(1,1,-dimethylethyl)-4-[[2-(5H-imidazo-[4,5-c]pyridin-5-yl)propyl]thio]-phenol hydrate (X═H2—CH2—; Y=bond; R1=hydrogen, R2═H, R3=thioaryl substituted with three R6, wherein R6=2 branched C4alkyl in meta and OH in para) (as disclosed in example 6 of WO96/12703);
(j) The compound is 5-[2-(Biphenyl-4-yloxy)-ethyl]-5H-imidazo[4,5-c]pyridine (X═CH2CH2, Y=bond, R1=hydrogen, R2═H, R3=phenoxy substituted with 1 R17 in para, wherein R17=benzyl; R4═H) (as disclosed in WO96/11192);
(k) The compound is 5-[2-(4-Phenoxy-phenoxy)-ethyl]-5H-imidazo[4,5-c]pyridine (X═CH2CH2, Y=bond, R1=hydrogen, R2═H, R3=phenoxy substituted with 1 R17 in para, wherein R17=phenoxy ;R4═H) (as disclosed in WO96/11192);
(l) The compound is [5-(4-Fluorobenzyl)-5H-imidazo[4,5-c]pyridin-2-yl]-methylamine (X═CH2, Y═NR11, wherein R11=methyl, R1═R2═H, R3=phenyl substituted with 1 R17 in para, wherein R6 is F, R4═H, R5═H) (as disclosed in EP76530);
(m) The compound is 2,6-bis(1,1,-dimethylethyl)-4-[[3-(5H-imidazo-[4,5-c]pyridin-5-yl)propyl]thio]-phenol hydrate (X═CH2—CH2—CH2, Y=bond; R1=hydrogen, R2═H, R3=thiophenyl substituted with 3 R6, wherein R6=2 branched C4 alkyl in meta and OH in para) (as disclosed in WO96/12703);
(n) The compound is 5-[2-(4-Phenylmethyloxy-phenoxy)-ethyl]-5H-imidazo[4,5-c]pyridine (X═CH2CH2, Y=bond, R1=hydrogen, R2═H, R3=phenoxy substituted with 1 R17 in para, wherein R17=benzyl oxy) (as disclosed in WO96/11192);
(o) The compound is 5-[3-(4-Phenoxy-phenoxy)-propyl]-5H-imidazo[4,5-c]pyridine (X═CH2CH2CH2, Y=bond, R1=hydrogen, R2═H, R3=phenoxy substituted with 1 R6 in para, wherein R6=phenoxy substituted in para with F; R4═H) (as disclosed in WO96/11192);
(p) The compound is 5-{2-[4-(4-Fluorophenoxy)-phenoxy]-ethyl}-5H-imidazo[4,5-c]pyridine (X═CH2CH2, Y=bond, R1=hydrogen, R2═H, R3=phenoxy substituted with 1 R6 in para, wherein R6=phenoxy, substituted in para with F; R4═H) (as disclosed in WO96/11192);
(q) The compound is 5-[3-(4-Phenylmethyl-phenoxy)-propyl]-5H-imidazo[4,5-c]pyridine (X═CH2CH2CH2, Y=bond, R1=hydrogen, R2═H, R3=phenoxy substituted with 1 R6 in para, wherein R6=benzyl; R4═H) (as disclosed in WO96/11192);
(r) The compound is (1H-Indol-3-yl)-[3-(2-methyl-5H-imidazo[4,5-c]pyridine-5-carbonyl)-phenyl]-methanone (X═—(C═O)— or SO2, Y═CH2, R1═H, R2═H, R3=phenyl substituted with 1 R6, wherein R6 is C(═O)R18, wherein R18 is indole) (as disclosed in U.S. Pat. No. 5,486,525);
(s) The compound is 4 or 3-[(2-methyl-5H-imidazo[4,5-c]pyridin-5-yl)methyl]-benzoic acid alkylester or 5-[4 or 3-(alkoxycarbonyl-phenyl)-methyl]-2-methyl-5H-imidazo[4,5-c]pyridine, in particular 4 or 3-[(2-methyl-5H-imidazo[4,5-c]pyridin-5-yl)methyl]-methyl ester (X═CH2, Y═CH2, R1═H, R2═H, R3=phenyl substituted at the para or meta position with one R17, wherein R17 is (C═O)R18, wherein R18=alkoxy) (as disclosed in U.S. Pat. No. 5,486,525) (t) The compound is 5-[(fluorophenyl)methyl]-2-amino-5-H-imidazo[4,5-c]-pyridine (XR3=fluorobenzyl, Y═NR11 with R11=methyl, R1═H, R2, R3, R4═H) (as disclosed in U.S. Pat. No. 5,137,896);
(u) The compound is ((5-[4(Fluorophenyl)methyl]-5-H-imidazo[4,5-c]-pyridine-2-yl) methyl)-carbamate, methyl ester (XR3=fluorobenzyl, Y═C(═O)R12 with R12=methyl, R1═H, R2, R3, R4═H) (as disclosed in U.S. Pat. No. 5,137,896);
(v) The compound is 5-(4-Chlorophenylmethyl)-2-piperidin-1-ylmethyl)-5H-imidazo[4,5-c]pyridine and its dihydrochloride salt (XR3=chlorobenzyl, Y═—CH2—, R1=piperidinyl) (as disclosed in Justus Liebigs Annalen der Chemie (1971), 747, 158-171);
(w) The compound is 5-(4-Chlorophenylmethyl)-2-(4-methyl-piperazin-1-ylmethyl)-5H-imidazo[4,5-c]pyridine (XR3=chlorobenzyl, Y═—CH2—, R1=piperazinyl, R6=methyl) (as disclosed in Journal of the Chemical Society [section B]: Physical Organic (1966), 4, 285-291);
(x) Compounds, particularly compound 9 on page 160, Cleve et al. “Liebigs Ann. Chem. 747:158-171 (1971);
(y) Compounds, particularly compounds 19 and 20, of Kiyama et al. “Chem. Pharm. Bull. 43(3):450-460 (1995); and
(z) Compounds, particularly compound 14, of Medereski et al. “Tet Lt.” 48(48): 10549-10558 (1992)
The compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein (a) Y R1 is not phenyl para substituted with OH, or (b) is H, an unsubstituted C3-10 cycloalkyl, or C1-6 alkyl.
The compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R1 is not H, Y is not NR11 with R11 C1-6 alkyl or methyl, and/or YR1 is not monomethylamino.
The compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R1 is a phenyl substituted with 1R6, R6 is C(═O)R18 and R18 is t-butoxy.
The compounds of the invention optionally exclude those compounds according to the general formula (A) as described above, wherein R1 is not piperidinyl and is not piperazinyl substituted with methyl.
The compounds of this invention exclude those compounds disclosed by WO 2004/005286, in particular the compounds in table 8 thereof.
The compounds of this invention optionally exclude those in which XR3 is the definitional equivalent to the substructure —(CH2)n—Y—C(O)—N(R1)(R2) set forth on column 1, line 49 to column 2 line 38 of U.S. Pat. No. 5,302,601 and the comparable disclosure in any member of the patent family of U.S. Pat. No. 5,302,601, which disclosure is herewith expressly incorporated by reference.
The compounds of this invention optionally exclude those in which R5 contains any of the substituents designated as <<Ar>> in WO 00/39127, in particular aryl, aryl phenoxy, or benzyl.
The compounds of this invention optionally do not include the compounds of Example 35 of U.S. Pat. No. 5,302,601, Example 6 of U.S. Pat. No. 4,990,518, Examples 1 to 5 of U.S. Pat. No. 4,988,707, Examples 1-5 of U.S. Pat. No. 5,208,241, Example 39 of U.S. Pat. No. 5,137,896, the azabenzimidazole compound of WO 99/27929, Examples 1-20 and 45 of U.S. Pat. No. 5,227,384, Examples 3 and/or 11 of WO 96/12703 and/or compounds 340A, 347C, 349C, 351C, 355C and/or 356 C of WO 96/11192.
The compounds of this invention optionally exclude those in which XR3 is equivalent to the substructure —(CH2)n-Het-C(O)—N(R1)(R2) set forth on column 1, line 41 to column 2 line 24 of U.S. Pat. No. 4,990,518.
The compounds of this invention do not include the compounds expressly disclosed in the patents listed in the Background of the Invention above, in Chemical Abstracts acc no. 1987:18435 and in Chemical Abstracts acc no. 1983:594812.
The compounds of this invention do not include the compounds expressly disclosed in Justus Liebigs Annalen der Chemie (1971), 747, 158-171 or in the Journal of the Chemical Society [section B]: Physical Organic (1966), 4, 285-291.
Optionally, the compounds of this invention exclude those compounds wherein YR1 is one of the substitutents designated R13 in column 5, lines 22-38 of U.S. Pat. No. 5,486,525 and/or R2 and/or R5 are one of the substituents collectively designated R14 and R15 in column 5, lines 38-53 of U.S. Pat. No. 5,486,525.
Optionally, the compounds of this invention exclude the compounds found in any patent family member of any published or issued patent specifically recited in this application.
Finally, the compounds of this invention optionally also exclude the methylene homologues of the foregoing known compounds excluded from the scope of this invention. It is understood that a compound optionally excluded also includes the salts thereof.
Utilities
The compounds of this invention, or the metabolites produced from these compounds in vivo, have a large number of uses. They are useful in immunology, chromatography, diagnostics and therapeutics, among other fields.
The compounds of formula (A) are conjugated to immunogenic polypeptides as a reagent for eliciting antibodies capable of binding specifically to the polypeptide, to the compounds or to their metabolic products which retain immunologically recognized epitopes (sites of antibody binding). These immunogenic compositions therefore are useful as intermediates in the preparation of antibodies for use in diagnostics, quality control, or the like, or in assays for the compounds of formula (A) or their novel metabolic products. The compounds are useful for raising antibodies against otherwise non-immunogenic polypeptides, in that the compounds serve as haptenic sites stimulating an immune response which cross-reacts with the unmodified conjugated protein.
Conjugates of the compounds of formula (A) with immunogenic polypeptides such as albumin or keyhole limpet hemocyanin generally are useful as immunogens. The polypeptides are conjugated at the same sites denoted for amino acids. The metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention Thus, the antibodies of this invention will be capable of binding to the unprotected compounds of the invention without binding to the protected compounds. Alternatively the metabolic products will be capable of binding to the protected compounds and/or the metabolitic products without binding to the protected compounds of the invention, or will be capable of binding specifically to any one or all three. The antibodies desirably will not substantially cross-react with naturally-occurring materials. Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes sufficient to interfere with the assay results.
The immunogens of this invention contain the compound of this invention presenting the desired epitope in association with an immunogenic substance. Within the context of the invention such association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above. Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and immunogenic polysaccharides. Typically, the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent. Methods for the manufacture of hapten immunogens are conventional per se, and any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to the epitope in question as opposed to the immunogenic substance.
Typically the polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized.
The conjugates are prepared in conventional fashion. For example, the cross-linking agents N-hydroxysuccinimide, succinic anhydride or alkN═C═Nalk are useful in preparing the conjugates of this invention. The conjugates comprise a compound of the invention attached by a bond or a linking group of 1-100, typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance. The conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage.
Animals are typically immunized against the immunogenic conjugates or derivatives and antisera or monoclonal antibodies prepared in conventional fashion.
The compounds of this invention are useful as linkers, spacers or affnity (typically hydrophobic) moieties in preparing affinity absorption matrices. The compounds of the invention optionally are bound covalently to an insoluble matrix and used for affinity cbromatography separations, depending on the nature of the groups of the compounds, for example compounds with pendant aryl groups are useful in making hydrophobic affinity columns.
They also are useful as linkers and spacers in preparing immobilized enzymes for process control, or in making immunoassay reagents. The compounds herein contain functional groups that are suitable as sites for cross-linking desired substances. For example, it is conventional to link affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates. These insolublized reagents are employed in known fashion to absorb binding partners for the affinity reagents from manufactured preparations, diagnostic samples and other impure mixtures. Similarly, immobilized enzymes are used to perform catalytic conversions with facile recovery of enzyme. Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
The compounds of this invention are labeled with detectable moieties such biotin, radioisotopes, enzymes and the like for diagnostic purposes. Suitable techniques for accomplishing the labeling of the compounds of formula (A) are well known and will be apparent to the artisan from consideration of this specification as a whole. For example, one suitable site for labeling is R17 or R19.
More typically, however, the compounds of the invention are employed for the treatment or prophylaxis of viral infections such as yellow fever virus, Dengue virus, hepatitis B virus, hepatitis G virus, Classical Swine Fever virus or the Border Disease Virus, but more particularly flaviviral or picornaviral infections, in particular, HCV and BVDV.
The therapeutic compound(s) of this invention are administered to a subject mammal (including a human) by any means well known in the art, i.e. orally, intranasally, subcutaneously, intramuscularly, intradermally, intravenously, intra-arterially, parenterally or by catheterization. The therapeutically effective amount of the compound(s) is a flaviviral or picornaviral growth inhibiting amount. More preferably, it is a flaviviral or picornaviral replication inhibiting amount or a flaviviral or picornaviral enzyme inhibiting amount of the compounds of formula (A). This is believed to correspond to an amount which ensures a plasma level of between about 1 μg/ml and 100 mg/ml, optionally of 10 mg/ml. This optionally is achieved by administration of a dosage of in the range of 0.001 mg to 60 mg, preferably 0.01 mg to 10 mg, preferably 0.1 mg to 1 mg per day per kg bodyweight for humans. These are starting points for determining the optimal dosage of the compound of this invention. The actual amount will depend upon many factors known to the artisan, including bioavailability of the compound, whether it contains a prodrug functionality, its metabolism and distribution in the subject and its potency, among others. It typically is necessary to determine the proper dosing in the clinical setting, and this is well within the skill of the ordinary artisan. The therapeutically effective amount of the compound(s) of this invention optionally are divided into several sub-units per day or are administered at daily or more than one day intervals, depending upon the pathologic condition to be treated, the patient's condition and the nature of the compound of this invention.
As is conventional in the art, the evaluation of a synergistic effect in a drug combination may be made by analyzing the quantification of the interactions between individual drugs, using the median effect principle described by Chou et al. in Adv. Enzyme Reg. (1984) 22:27 or tests such as, but not limited to, the isobologram method, as previously described by Elion et al. in J. Biol. Chem. (1954) 208:477-488 and by Baba et al. in Antimicrob. Agents Chemother. (1984) 25:515-517, using EC50 for calculating the fractional inhibitory concentration.
Suitable anti-viral agents for inclusion in combination antiviral compositions or for coadministration in a course of therapy include, for instance, interferon alpha, ribavirin, a compound falling within the scope of disclosure of EP 1162196, WO 03/010141, WO 03/007945 and WO 03/010140, a compound falling within the scope of disclosure of WO 00/204425, and other patents or patent applications within their patent families, in amounts of 1 to 99.9% by weight compound of this invention, preferably from 1 to 99% by weight, more preferably from 5 to 95% by weight as can be readily determined by one skilled in the art. Such co-admmistered agents need not be formulated in the same dosage form as the compound of the invention. They optionally are simply administered to the subject in the course of treatment along with a course of treatment with a compound of formula (A).
The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore, for example in the treatment of BVDV. Veterinary carriers are materials useful for the purpose of administering the composition and are excipients which are otherwise inert or acceptable in the veterinary art and are compatible with the compound of this invention. These veterinary compositions maybe administered orally, parenterally or by any other desired route.
Salts
The term “pharmaceutically acceptable salts” as used herein means the therapeutically active non-toxic salt forms formed by the compounds of formula (A). Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
The compounds of the invention may bear multiple positive or negative charges. The net charge of the compounds of the invention may be either positive or negative. Any associated counter ions are typically dictated by the synthesis and/or isolation methods by which the compounds are obtained. Typical counter ions include, but are not limited to ammonium, sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc., and mixtures thereof. It will be understood that the identity of any associated counter ion is not a critical feature of the invention, and that the invention encompasses the compounds in association with any type of counter ion Moreover, as the compounds can exist in a variety of different forms, the invention is intended to encompass not only forms of the compounds that are in association with counter ions (e.g., dry salts), but also forms that are not in association with counter ions (e.g., aqueous or organic solutions).
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, Ca+2 and Mg+2 and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids to basic centers, typically amines, or to acidic groups. Examples of such appropriate acids include, for instance, inorganic acids such as hydrohalogen acids, e.g. hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, benzoic, 2-hydroxypropanoic, 2-oxopropanoic, lactic, fumaric, tartaric, pyruvic, maleic, malonic, malic, salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic, isethionic, lactobionic, succinic oxalic and citric acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids, C1-C6 ailylsulfonic, benzenesulfonic, p-toluenesuifonic, cyclohexanesulfamic, and the like. Preferred salts include mesylate and HCl.
The compounds of this invention include the solvates formed with the compounds of formula (A) and their salts, such as for example hydrates, alcoholates and the like. The compositions herein comprise compounds of the invention in their unionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the compounds of formula (A) with one or more amino acids as described above. The amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
Salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a compound of formula (A). All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
Isomers
The term “isomers” as used herein means all possible isomeric forms, including tautomeric and stereochemical forms, which the compounds of formula (A) may possess, but not including position isomers. Typically, the structures shown herein exemplify only one tautomeric or resonance form of the compounds, but the corresponding alternative configurations are contemplated as well. Unless otherwise stated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers (since the compounds of formula (A) may have one or more chiral centers), as well as the stereochemically pure or enriched isomers. More particularly, stereogenic centers may have either the R- or S-configuration, and double or triple bonds optionally are in either the cis- or trans-configuration.
Enriched isomeric forms of a compound of this invention are defined as a single isomer substantially free of the compound's other enantiomers or diastereomers. In particular, the term “stercoisomericahy enriched” or “chirally enriched” relates to compounds having a single stereoisomeric proportion of at least about 80% (i.e. at least 90% of one isomer and at most 10% of the other possible isomers), preferably at least 90%, more preferably at least 94% and most preferably at least 97%. The terms “enantiomerically pure” and “diastereomerically pure” contain undetectable levels of any other isomer.
Separation of stereoisomers is accomplished by standard methods known to those in the art. One enantiomer of a compound of the invention can be separated substantially free of its opposing enantiomer by a method such as formation of diastereomers using optically active resolving agents (“Stereochemistry of Carbon Compounds,” (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Separation of isomers in a mixture can be accomplished by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure enantiomers, or (3) enantiomers can be separated directly under chiral conditions. Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl-b-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing an acidic functionality, such as carboxylic acid and sulfonic acid.
The diastereomeric salts optionally are induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. Alternatively, by method (2), the substrate to be resolved may be reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994). Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene. A method of determining optical purity involves making chiral esters, such as a menthyl ester or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). Under method (3), a racemic mixture of two asymmetric enantiomers is separated by chromatography using a chiral stationary phase. Suitable chiral stationary phases are, for example, polysaccharides, in particular cellulose or amylose derivatives. Commercially available polysaccharide based chiral stationary phases are ChiralCeI™ CA, OA, OB5, OC5, OD, OF, OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriate eluents or mobile phases for use in combination with said polysaccharide chiral stationary phases are hexane and the like, modified with an alcohol such as ethanol, isopropanol and the like. (“Chiral Liquid Chromatography” (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990). “Optical resolution of dihydropyridine enantiomers by High-performance liquid chromatography using phenylcarbamates of polysaccharides as a chiral stationary phase”, J. of Chromatogr. 513:375-378).
Metabolites
The present invention also provides the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. C14 or H3) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no antiviral activity of their own.
Formulations
The compounds of the invention optionally are formulated with conventional pharmaceutical carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. Formulations optionally contain excipients such as those set forth in the “Handbook of Pharmaceutical Excipiexits” (1986) and include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
Subsequently, the term “pharmaceutically acceptable carrier” as used herein means any material or substance with which the active ingredient is formulated in order to facilitate its application or dissemination to the locus to be treated, for instance by dissolving, dispersing or diffusing the said composition, and/or to facilitate its storage, transport or handling without impairing its effectiveness. The pharmaceutically acceptable carrier may be a solid or a liquid or a gas which has been compressed to form a liquid, i.e. the compositions of this invention can suitably be used as concentrates, emulsions, solutions, granulates, dusts, sprays, aerosols, suspensions, ointments, creams, tablets, pellets or powders.
Suitable pharmaceutical carriers for use in the said pharmaceutical compositions and their formulation are well known to those skilled in the art, and there is no particular restriction to their selection within the present invention. They may also include additives such as wetting agents, dispersing agents, stickers, adhesives, emulsifying agents, solvents, coatings, antibacterial and antifungal agents (for example phenol, sorbic acid, chlorobutanol), isotonic agents (such as sugars or sodium chloride) and the like, provided the same are consistent with pharmaceutical practice, i.e. carriers and additives which do not create permanent damage to mammals. The pharmaceutical compositions of the present invention may be prepared in any known manner, for instance by homogeneously mixing, coating and/or grinding the active ingredients, in a one-step or multi-steps procedure, with the selected carrier material and, where appropriate, the other additives such as surface-active agents may also be prepared by micronisation, for instance in view to obtain them in the form of microspheres usually having a diameter of about 1 to 10 gm, namely for the manufacture of microcapsules for controlled or sustained release of the active ingredients.
Suitable surface-active agents, also known as emulgent or emulsifier, to be used in the pharmaceutical compositions of the present invention are non-ionic, cationic and/or anionic materials having good emulsifying, dispersing and/or wetting properties. Suitable anionic surfactants include both water-soluble soaps and water-soluble synthetic surface-active agents. Suitable soaps are alkaline or alkaline-earth metal salts, unsubstituted or substituted ammonium salts of higher fatty acids (C10 -C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures obtainable form coconut oil or tallow oil. Synthetic surfactants include sodium or calcium salts of polyacrylic acids; fatty sulphonates and sulphates; sulphonated benzimidazole derivatives and allylarylsulphonates. Fatty sulphonates or sulphates are usually in the form of alkaline or alkaline-earth metal salts, unsubstituted ammonium salts or ammonium salts substituted with an alkyl or acyl radical having from 8 to 22 carbon atoms, e.g. the sodium or calcium salt of lignosulphonic acid or dodecylsulphonic acid or a mixture of fatty alcohol sulphates obtained from natural fatty acids, alkaline or alkaline-earth metal salts of sulphuric or sulphonic acid esters (such as sodium lauryl sulphate) and sulphonic acids of fatty alcohol/ethylene oxide adducts. Suitable sulphonated benzimidazole derivatives preferably contain 8 to 22 carbon atoms. Examples of alkylarylsulphonates are the sodium, calcium or alcoholamine salts of dodecylbenzene sulphonic acid or dibutyl-naphthalenesulphonic acid or a naphthalene-sulphonic acid/formaldehyde condensation product. Also suitable are the corresponding phosphates, e.g. salts of phosphoric acid ester and an adduct of p-nonylphenol with ethylene and/or propylene oxide, or phospholipids. Suitable phospholipids for this purpose are the natural (originating from animal or plant cells) or synthetic phospholipids of the cephalin or lecitlun type such as e.g. phosphatidylethanolamine, phosphatidylserine, pliosphatidylglycerine, lysolecithin, cardiolipin, dioctanylphosphatidyl-choline, dipalmitoylphoshatidyl-choline and their mixtures.
Suitable non-ionic surfactants include polyethoxylated and polypropoxylated derivatives of alkylphenols, fatty alcohols, fatty acids, aliphatic amines or amides containing at least 12 carbon atoms in the molecule, alkylarenesulphonates and dialkylsulfosuccinates, such as polyglycol ether derivatives of aliphatic and cycloaliphatic alcohols, saturated and unsaturated fatty acids and alkylphenols, said derivatives preferably containing 3 to 10 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenol. Further suitable non-ionic surfactants are water-soluble adducts of polyethylene oxide with poylypropylene glycol, ethylenediaminopolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethyleneglycol ether groups and/or 10 to 100 propyleneglycol ether groups. Such compounds usually contain from 1 to 5 ethyleneglycol units per propyleneglycol unit. Representative examples of non-ionic surfactants are nonylphenol-polyethoxyethanol, castor oil polyglycolic ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethyleneglycol and octylphenoxypolyethoxyethainol. Fatty acid esters of polyethylene sorbitan (such as polyoxyethylene sorbitan trioleate), glycerol, sorbitan, sucrose and pentaerythritol are also suitable non-ionic surfactants.
Suitable cationic surfactants include quaternary ammonium salts, particularly halides, having 4 hydrocarbon radicals optionally substituted with halo, phenyl, substituted phenyl or hydroxy; for instance quaternary ammonium salts containing as N-substituent at least one C8C22 alkyl radical (e.g. cetyl, lauryl, palmityl, myristyl, oleyl and the like) and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl and/or hydroxy-lower alkyl radicals.
A more detailed description of surface-active agents suitable for this purpose may be found for instance in “McCutcheon's Detergents and Emulsifiers Annual” (MC Publishing Crop., Ridgewood, N.J., 1981), “Tensid-Taschenbucw”, 2 d ed (Hanser Verlag, Vienna, 1981) and “Encyclopaedia of Surfactants, (Chemical Publishing Co., New York, 1981).
Compounds of the invention and their physiologically acceptable salts (hereafter collectively referred to as the active ingredients) may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural). The preferred route of administration may vary with for example the condition of the recipient.
While it is possible for the active ingredients to be administered alone it is preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the present invention comprise at least one active ingredient, as above described, together with one or more pharmaceutically acceptable carriers therefore and optionally other therapeutic ingredients. The carrier(s) optimally are “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. For infections of the eye or other external tissues e.g. mouth and skin, the formulations are optionally applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Optionally, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus the cream should optionally be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl paliutate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is optionally present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.), which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention (“controlled release formulations”) in which the release of the active ingredient can be controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given invention compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
Additional ingredients may be included in order to control the duration of action of the active ingredient in the composition. Control release compositions may thus be achieved by selecting appropriate polymer carriers such as for example polyesters, polyamino acids, polyvinyl pyrrolidone, ethylene-vinyl acetate copolymers, methylcellulose, carboxymethylceelulose, protamne sulfate and the like. The rate of drug release and duration of action may also be controlled by incorporating the active ingredient into particles, e.g. microcapsules, of a polymeric substance such as hydrogels, polylactic acid, hydroxymethylcellulose, polymethyl metliacrylate and the other above-described polymers. Such methods include colloid drug delivery systems like liposomes, microspheres, microemulsioas, nanoparticles, nanocapsules and so on. Depending on the route of administration, the pharmaceutical composition may require protective coatings. Pharmaceutical forms suitable for injectionable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation thereof. Typical carriers for this purpose therefore include biocompatible aqueous buffers, ethanol, glycerol, propylene glycol, polyethylene glycol and the like and mixtures thereof.
In view of the fact that, when several active ingredients are used in combination, they do not necessarily bring out their joint therapeutic effect directly at the same time in the mammal to be treated, the corresponding composition may also be in the form of a medical kit or package containing the two ingredients in separate but adjacent repositories or compartments. In the latter context, each active ingredient may therefore be formulated in a way suitable for an administration route different from that of the other ingredient, e.g. one of them may be in the form of an oral or parenteral formulation whereas the other is in the form of an ampoule for intravenous injection or an aerosol.
Synthetic Methods
The compounds of formula (A) are prepared using a series of chemical reactions well known to those skilled in the art, altogether making up the process for preparing said compounds and exemplified further. The processes described further are only meant as examples and by no means are meant to limit the scope of the present invention.
The invention also relates to methods of making the compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in “Compendium of Organic Synthetic Methods” (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., “Advanced Organic Chemistry, Third Edition”, (John Wiley & Sons, New York, 1985), “Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes”, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing).
Exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations, and are not intended to limit the scope of applicable methods.
Generally, the reaction conditions such as temperature, reaction time, solvents, workup procedures, and the lice, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be −100° C. to 200° C., solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20° C.), although for metal hydride reductions frequently the temperature is reduced to 0° C. to −100° C., solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0° C. to −100° C.) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
General aspects of these exemplary methods are described below. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsequent processes.
The terms “treated”, “treating”, “treatment”, and the like, mean contacting, nixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that “treating compound one with compound two” is synonymous with “allowing compound one to react with compound two”, “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react”, etc., with compound two.
“Treating” indicates the reasonable and usual manner in which organic chemicals are allowed to react. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (−100° C. to 250° C., typically −78° C. to 150° C, more typically −78° C. to 100° C., still more typically 0° C. to 100° C.), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis is used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic sysnthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
Modification of the exemplified schemes and examples leads to various analogs of the specific exemplary materials produced above. The above citations describing suitable methods of organic synthesis are applicable to such modifications.
In the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.
Suitable methods for making the compounds of this invention also are found in WO 2004/005286, in particular schemes 1-13 therein.
Another synthetic route to 5-benzyl-2-phenyl-5H-imidazo[4,5-c]pyridine and analogues is shown in scheme 1.
Figure US08329727-20121211-C00009
The following list includes carboxylic acid reactants which may be employed in the condensation, ring closure reaction of Scheme 1. The compounds so produced will bear the residue of the acid at the site of YR1. Optionally, the remainder of the molecule will be as in any of the compounds of examples 2-7.
Acid MW
Figure US08329727-20121211-C00010
 		258.117
Figure US08329727-20121211-C00011
 		258.117
Figure US08329727-20121211-C00012
 		158.103
Figure US08329727-20121211-C00013
 		174.558
Figure US08329727-20121211-C00014
 		191.013
Figure US08329727-20121211-C00015
 		214.219
Figure US08329727-20121211-C00016
 		152.148
Figure US08329727-20121211-C00017
 		179.199
Figure US08329727-20121211-C00018
 		124.099
Figure US08329727-20121211-C00019
 		156.204
Figure US08329727-20121211-C00020
 		189.173
Figure US08329727-20121211-C00021
 		113.072
Figure US08329727-20121211-C00022
 		146.144
Figure US08329727-20121211-C00023
 		137.137
Figure US08329727-20121211-C00024
 		244.22
Figure US08329727-20121211-C00025
 		164.159
Figure US08329727-20121211-C00026
 		190.12
Figure US08329727-20121211-C00027
 		191.013
Figure US08329727-20121211-C00028
 		165.191
Figure US08329727-20121211-C00029
 		214.219
Figure US08329727-20121211-C00030
 		206.118
Figure US08329727-20121211-C00031
 		194.229
Figure US08329727-20121211-C00032
 		174.158
Figure US08329727-20121211-C00033
 		200.213
Figure US08329727-20121211-C00034
 		200.213
Figure US08329727-20121211-C00035
 		252.272
Figure US08329727-20121211-C00036
 		250.256
Figure US08329727-20121211-C00037
 		216.21
Figure US08329727-20121211-C00038
 		216.21
Figure US08329727-20121211-C00039
 		277.116
Figure US08329727-20121211-C00040
 		164.159
Figure US08329727-20121211-C00041
 		178.23
Figure US08329727-20121211-C00042
 		125.126
Figure US08329727-20121211-C00043
 		112.084
Figure US08329727-20121211-C00044
 		128.151
Figure US08329727-20121211-C00045
 		124.099
Figure US08329727-20121211-C00046
 		200.213
Figure US08329727-20121211-C00047
 		201.201
Figure US08329727-20121211-C00048
 		112.088
Figure US08329727-20121211-C00049
 		215.251
Figure US08329727-20121211-C00050
 		215.251
Figure US08329727-20121211-C00051
 		126.114
Figure US08329727-20121211-C00052
 		129.139
Figure US08329727-20121211-C00053
 		143.165
Figure US08329727-20121211-C00054
 		124.099
Figure US08329727-20121211-C00055
 		127.099
Figure US08329727-20121211-C00056
 		126.114
Figure US08329727-20121211-C00057
 		222.238
Figure US08329727-20121211-C00058
 		124.099
Figure US08329727-20121211-C00059
 		174.158
Figure US08329727-20121211-C00060
 		240.257
Figure US08329727-20121211-C00061
 		166.175
Figure US08329727-20121211-C00062
 		137.137
Figure US08329727-20121211-C00063
 		204.267
Figure US08329727-20121211-C00064
 		141.101
Figure US08329727-20121211-C00065
 		174.158
Figure US08329727-20121211-C00066
 		230.266
Figure US08329727-20121211-C00067
 		221.279
Figure US08329727-20121211-C00068
 		257.107
Figure US08329727-20121211-C00069
 		223.614
Figure US08329727-20121211-C00070
 		140.141
Figure US08329727-20121211-C00071
 		176.17
Figure US08329727-20121211-C00072
 		154.139
Figure US08329727-20121211-C00073
 		173.17
Figure US08329727-20121211-C00074
 		173.17
Figure US08329727-20121211-C00075
 		178.21
Figure US08329727-20121211-C00076
 		187.197
Figure US08329727-20121211-C00077
 		173.17
Figure US08329727-20121211-C00078
 		154.139
Figure US08329727-20121211-C00079
 		188.128
Figure US08329727-20121211-C00080
 		262.21
Figure US08329727-20121211-C00081
 		187.197
Figure US08329727-20121211-C00082
 		178.15
Figure US08329727-20121211-C00083
 		176.17
Figure US08329727-20121211-C00084
 		157.556
Figure US08329727-20121211-C00085
 		234.2
Figure US08329727-20121211-C00086
 		112.088
Figure US08329727-20121211-C00087
 		192.169
Figure US08329727-20121211-C00088
 		187.197
Figure US08329727-20121211-C00089
 		170.138
The following list includes alkylating reagents which may be employed in the pyridyl alkylation reaction of Scheme 1. Here, the residue of the alkylating agent is located at the X R3 site of the compound of this invention. Optionally, the remainder of the compound will be as found in any of the compounds of examples 2-7.
Alkylating reagent MW
Figure US08329727-20121211-C00090
 		195.475
Figure US08329727-20121211-C00091
 		168.666
Figure US08329727-20121211-C00092
 		154.639
Figure US08329727-20121211-C00093
 		154.639
Figure US08329727-20121211-C00094
 		145.588
Figure US08329727-20121211-C00095
 		190.672
Figure US08329727-20121211-C00096
 		338.832
Figure US08329727-20121211-C00097
 		205.039
Figure US08329727-20121211-C00098
 		325.225
Figure US08329727-20121211-C00099
 		262.579
Figure US08329727-20121211-C00100
 		228.721
Figure US08329727-20121211-C00101
 		207.016
Figure US08329727-20121211-C00102
 		307.03
Figure US08329727-20121211-C00103
 		199.09
Figure US08329727-20121211-C00104
 		175.057
Figure US08329727-20121211-C00105
 		154.639
Figure US08329727-20121211-C00106
 		216.663
Figure US08329727-20121211-C00107
 		218.682
Figure US08329727-20121211-C00108
 		275.144
Figure US08329727-20121211-C00109
 		198.648
Figure US08329727-20121211-C00110
 		294.907
Figure US08329727-20121211-C00111
 		244.144
Figure US08329727-20121211-C00112
 		222.084
Figure US08329727-20121211-C00113
 		152.623
Figure US08329727-20121211-C00114
 		118.523
Figure US08329727-20121211-C00115
 		255.138
Figure US08329727-20121211-C00116
 		328.828
Figure US08329727-20121211-C00117
 		202.611
Figure US08329727-20121211-C00118
 		281.123
Figure US08329727-20121211-C00119
 		170.638
Figure US08329727-20121211-C00120
 		257.023
Figure US08329727-20121211-C00121
 		257.023
Figure US08329727-20121211-C00122
 		257.023
Figure US08329727-20121211-C00123
 		257.023
Figure US08329727-20121211-C00124
 		257.023
Figure US08329727-20121211-C00125
 		257.023
Figure US08329727-20121211-C00126
 		255.032
Figure US08329727-20121211-C00127
 		174.63
Figure US08329727-20121211-C00128
 		186.637
Figure US08329727-20121211-C00129
 		247.134
Figure US08329727-20121211-C00130
 		190.672
Figure US08329727-20121211-C00131
 		204.676
Figure US08329727-20121211-C00132
 		257.023
Figure US08329727-20121211-C00133
 		262.579
Figure US08329727-20121211-C00134
 		224.646
Figure US08329727-20121211-C00135
 		194.62
Figure US08329727-20121211-C00136
 		262.617
Figure US08329727-20121211-C00137
 		237.042
Figure US08329727-20121211-C00138
 		275.144
Figure US08329727-20121211-C00139
 		186.637
Figure US08329727-20121211-C00140
 		169.035
Figure US08329727-20121211-C00141
 		229.065
Figure US08329727-20121211-C00142
 		250.727
Figure US08329727-20121211-C00143
 		324.526
Figure US08329727-20121211-C00144
 		261.569
Figure US08329727-20121211-C00145
 		262.617
Figure US08329727-20121211-C00146
 		273.699
Figure US08329727-20121211-C00147
 		249.127
Figure US08329727-20121211-C00148
 		131.561
Figure US08329727-20121211-C00149
 		210.581
Figure US08329727-20121211-C00150
 		303.154
Figure US08329727-20121211-C00151
 		223.471
Figure US08329727-20121211-C00152
 		179.02
Figure US08329727-20121211-C00153
 		273.478
Figure US08329727-20121211-C00154
 		257.023
Figure US08329727-20121211-C00155
 		257.023
Figure US08329727-20121211-C00156
 		241.12
Figure US08329727-20121211-C00157
 		166.61
Figure US08329727-20121211-C00158
 		205.995
Figure US08329727-20121211-C00159
 		188.613
Figure US08329727-20121211-C00160
 		277.696
Figure US08329727-20121211-C00161
 		133.602
Figure US08329727-20121211-C00162
 		208.647
Figure US08329727-20121211-C00163
 		272.144
Figure US08329727-20121211-C00164
 		219.052
Figure US08329727-20121211-C00165
 		229.065
Figure US08329727-20121211-C00166
 		209.699
Figure US08329727-20121211-C00167
 		226.648
Figure US08329727-20121211-C00168
 		132.613
Figure US08329727-20121211-C00169
 		207.659
Figure US08329727-20121211-C00170
 		223.471
Figure US08329727-20121211-C00171
 		276.549
Figure US08329727-20121211-C00172
 		168.047
Figure US08329727-20121211-C00173
 		162.566
Figure US08329727-20121211-C00174
 		224.646
Figure US08329727-20121211-C00175
 		186.637
Figure US08329727-20121211-C00176
 		154.639
Figure US08329727-20121211-C00177
 		277.16
Figure US08329727-20121211-C00178
 		263.133
Figure US08329727-20121211-C00179
 		231.088
Figure US08329727-20121211-C00180
 		200.648
Figure US08329727-20121211-C00181
 		215.727
Figure US08329727-20121211-C00182
 		291.469
Figure US08329727-20121211-C00183
 		273.478
Figure US08329727-20121211-C00184
 		237.498
Figure US08329727-20121211-C00185
 		237.498
Figure US08329727-20121211-C00186
 		223.471
Figure US08329727-20121211-C00187
 		203.053
Figure US08329727-20121211-C00188
 		223.471
Figure US08329727-20121211-C00189
 		253.109
Figure US08329727-20121211-C00190
 		203.053
Figure US08329727-20121211-C00191
 		203.053
Figure US08329727-20121211-C00192
 		273.478
Figure US08329727-20121211-C00193
 		269.059
Figure US08329727-20121211-C00194
 		223.471
Figure US08329727-20121211-C00195
 		289.478
Figure US08329727-20121211-C00196
 		269.059
Figure US08329727-20121211-C00197
 		253.06
Figure US08329727-20121211-C00198
 		253.06
Figure US08329727-20121211-C00199
 		253.06
Figure US08329727-20121211-C00200
 		221.043
Figure US08329727-20121211-C00201
 		285.567
Figure US08329727-20121211-C00202
 		344.203
Figure US08329727-20121211-C00203
 		261.569
Figure US08329727-20121211-C00204
 		212.078
Figure US08329727-20121211-C00205
 		195.57
Figure US08329727-20121211-C00206
 		299.113
Figure US08329727-20121211-C00207
 		228.077
Figure US08329727-20121211-C00208
 		193.632
Figure US08329727-20121211-C00209
 		223.471
Figure US08329727-20121211-C00210
 		255.961
Figure US08329727-20121211-C00211
 		252.11
Figure US08329727-20121211-C00212
 		190.039
Figure US08329727-20121211-C00213
 		176.012
Figure US08329727-20121211-C00214
 		237.099
Figure US08329727-20121211-C00215
 		238.087
Figure US08329727-20121211-C00216
 		239.623
Figure US08329727-20121211-C00217
 		198.648
Figure US08329727-20121211-C00218
 		350.235
Figure US08329727-20121211-C00219
 		252.11
Figure US08329727-20121211-C00220
 		236.111
Figure US08329727-20121211-C00221
 		320.206
Figure US08329727-20121211-C00222
 		228.995
Figure US08329727-20121211-C00223
 		273.478
Figure US08329727-20121211-C00224
 		203.053
Figure US08329727-20121211-C00225
 		214.036
Figure US08329727-20121211-C00226
 		203.053
Figure US08329727-20121211-C00227
 		214.036
Figure US08329727-20121211-C00228
 		285.913
Figure US08329727-20121211-C00229
 		241.462
Figure US08329727-20121211-C00230
 		283.251
Figure US08329727-20121211-C00231
 		177.604
Figure US08329727-20121211-C00232
 		267.922
Figure US08329727-20121211-C00233
 		350.235
Figure US08329727-20121211-C00234
 		350.235
Figure US08329727-20121211-C00235
 		196.7
Figure US08329727-20121211-C00236
 		199.09
Figure US08329727-20121211-C00237
 		199.09
Figure US08329727-20121211-C00238
 		199.09
Figure US08329727-20121211-C00239
 		199.09
Figure US08329727-20121211-C00240
 		253.06
Figure US08329727-20121211-C00241
 		258.103
Figure US08329727-20121211-C00242
 		331.052
Figure US08329727-20121211-C00243
 		88.5365
Figure US08329727-20121211-C00244
 		132.988
Figure US08329727-20121211-C00245
 		102.563
Figure US08329727-20121211-C00246
 		144.644
ClH
Figure US08329727-20121211-C00247
 (hydrochloride salt)		 144.044
ClH
Figure US08329727-20121211-C00248
 		296.239
ClH
Figure US08329727-20121211-C00249
 		172.098
ClH
Figure US08329727-20121211-C00250
 		158.071
ClH
Figure US08329727-20121211-C00251
 		170.082
ClH
Figure US08329727-20121211-C00252
 		186.081
ClH
Figure US08329727-20121211-C00253
 		184.109
Figure US08329727-20121211-C00254
 		149.663
ClH
Figure US08329727-20121211-C00255
 		248.195
ClH
Figure US08329727-20121211-C00256
 		313.064
ClH
Figure US08329727-20121211-C00257
 		158.071
ClH
Figure US08329727-20121211-C00258
 		186.124
ClH
Figure US08329727-20121211-C00259
 		230.133
Figure US08329727-20121211-C00260
 		129.589
Figure US08329727-20121211-C00261
 ClH		 167.038
Figure US08329727-20121211-C00262
Figure US08329727-20121211-C00263
Figure US08329727-20121211-C00264
Figure US08329727-20121211-C00265
Figure US08329727-20121211-C00266
Figure US08329727-20121211-C00267
Figure US08329727-20121211-C00268
Figure US08329727-20121211-C00269
Figure US08329727-20121211-C00270
Figure US08329727-20121211-C00271
Figure US08329727-20121211-C00272
Figure US08329727-20121211-C00273
Figure US08329727-20121211-C00274
Figure US08329727-20121211-C00275
Figure US08329727-20121211-C00276
Figure US08329727-20121211-C00277
Figure US08329727-20121211-C00278
Figure US08329727-20121211-C00279
Figure US08329727-20121211-C00280
Figure US08329727-20121211-C00281
Figure US08329727-20121211-C00282
Scheme 2 shows a synthetic route to 5-biarylmethyl-2-phenyl-5H-imidazo[4,5-c]pyridines and 5-benzyl-2-biaryl-5H-imidazo[4,5-c]pyridines.
Figure US08329727-20121211-C00283
Scheme 3 shows a synthetic route to 5-(alkoxybenzyl)-2-phenyl-5H-imidazo[4,5-c]pyridines and 5-benzyl-2-alkoxybenzyl-5H-imidazo[4,5-c]pyridines. R, R′, and R″ can be any alkyl benzylic or heterobenzylic groups.
Figure US08329727-20121211-C00284
Analogous compounds may be synthesized in the same fashion as in the foregoing schemes by varying the starting materials, intermediates, solvents and conditions as will be known by those skilled in the art.
EXAMPLES Part A Compound Synthesis Example 1 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00285
Phosphorous pentoxide (24.56 g) was dissolved in methanesulfonic acid (165.8 mL) at 50° C. with stirring. To the solution, 3,4-diaminopyridine (12.3 g, 0.11 moles) and 2,3-difluorobenzoic acid (19.4 g, 0.12 moles) were added. The reaction mixture was heated to 190° C. for 3 hours. The reaction was done three times. The reaction mixtures was cooled to 50° C. and poured into ice with stirring. At this stage, all three batches were combined The reaction mixture was neutralized by the addition of NaOH with stirring until the pH is 8. Solid material precipitated out of solution, was collected by filtration and air-dried. The final product was recrystallized from ethanol/water twice to yield 36 g of 2-(2,3-difiluorophenyl)-3H-imidazo[4,5-c]pyridine. 1H 300 Mhz (CD3OD) sigma 7.3-7.42 (m, 1p); 7.43-7.58 (m, 1p); 7.70 (d, 1p); 8.0 (m, 1p); 8.34 (d, 1p); and 8.95 (s, 1p). LC/MS data M/z=232.
Following the above taught procedure and substituting 2-fluorobenzoic acid in place of 2,3-difluorobenzoic acid, the compound 2-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridine can be prepared.
Example 2 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00286
To a suspension of 2-(2-fluorophenyl)-3H-imidazo[4,5-c]pyridine (11.0 g, 50.0 mmoles) in DMF was added a 10% (w/v) solution of aqueous NaOH. To this solution, 5-(chloromethyl)-3-(4-chlorophenyl)isoxazole (13.68 g, 60.0 mmoles) dissolved in DMF was added. The reaction mixture was stirred at room temperature and monitored every half hour by LCMS. The reaction was stopped at 4 hours, after LCMS showed no progress between at 2 hour and 4 hour monitor points. The reaction product was triturated with first with water and then with EtoAc (3×). The material was crystallized by dissolving the material in MeOH with heat, followed by precipitation with water. This crystallization process was then repeated yielding 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine (15.385 g, 38 mmole) as white crystal at a yield of 74%. 1H 300 Mhz (d6-DMSO) sigma 6.02 (s, 2p); 7.13 (s, 1p); 7.26-7.35 (m, 2p); 7.43-7.52 (m, 1p); 7.56 (d, 2p); 7.84 (d, 1); 7.89 (d, 2p); 8.24 (d, 1); 8.28-8.36 (m, 1p); and 9.19 (s, 1p). LCMS data M/Z=405.31
Example 3A 5-(4-(trifluoromethoxy)benzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00287
First, 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine (20 g, 86.6 mmole) was added to 430 mL of DMF. Some of the solid material did not dissolve. To this solution was added 43 mL of a 10% NaOH (w/v) solution. With vigorous stirring, the un-dissolved material went into solution. The resulting solution was divided into 30 equal portions of 16.3 mL, 3 mmole of 2-(2,3-difluorophenyl)-3H-imidazo[4,5-c]pyridine so as to fit into a microwave reaction vessel. To each reaction vessel was added of 1-(chloromethyl)4-(trifluoromethoxy)benzene (693 mg, 3 mmole). Each reaction mixture was microwaved for 1 minute at 110° C. Following the completion of all the microwave reactions, all of the reaction vessels were combined (one was lost due to breakage of the vessel) into three batches for workup. For each batch, DMF was removed by vacuum, and the resulting material was washed three times with deionized water. The resulting crude material was dissolved in CH2Cl2, purified using a 330 g SiO2 column (Redisep (Isco) 0% to 0%/5 min to 10%/B/30 nin to 20%/5 min), and the resulting material was re-crystallized from ethanol/H2O. The three batches yielded 14 g, 33.5 mmole of 5-(4-(trifluoromethoxy)benzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine. 1H 300 Mhz (CD3OD) sigma 5.79 (s, 2p); 7.25-7.35 (m, 1p); 7.37 (d, 2p); 7.38-7.42 (m, 2p); 7.55 (d, 2p); 7.88-7.95 (m, 1p); 8.25 (d, 1p); and 9.05 (s, 1p). LC/MS M/z=406.23.
Example 3B
Following the above-taught procedure, and substituting 1-(chloromethyl)-2,4 difluorobenzene in place of 1-(chloromethyl)-4-(trifluoromethoxy)benzene, the compound 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine can be prepared.
Example 4 5-(2,4-difluoro-biphenyl)methyl-2-(2,3-difluorophenyl) -5H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00288
2,4-difluorophenylboronic acid (196 mg, 1.24 mmole) was added to a solution of 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (460 mg, 1.03 mmole) in DMF (10 mL). Na2CO3 was dissolved in H2O, added to the DMF solution and stirred Pd(PPh3)4 was then added to the DMF reaction mixture. The reaction mixture was heated in a microwave at 200° C. for 2 minutes. After extractive work-up using ethyl acetate/water, the crude product was purified in two batches using an Isco 40 g SiO2 column (0 to 10% B/20 min, A=CH2Cl2, B=MeOH, flow rate=40 ml/min) for each purification. The pure product fractions were combined and concentrated. The resulting solid was re-crystallized from CH2Cl/hexane. The collected crystals were dried under high vacuum overnight resulting in 5-(2,4-difluoro-biphenyl)methyl-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (223 mg, 0.515mmole) at 50% yield. 1H 300 Mhz (CD3OD) sigma 5.8 (s, 2p); 7.0-7.1 (m, 2p); 7.25-7.35 (m, 1p); 7.35-7.45 (m, 1p); 7.45-7.60 (m, 5p); 7.85 (d, 1p); 7.85-8.0 (m, 1p); 8.3 (d, 1p); and 9.10 (s, 1p). LC/MS data M/z=434.18.
Example 5 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00289
To a solution of azabenzimidazole (10 g, 43.3 mmole) in DMF was added 10% (w/v) aqueous NaOH followed by a solution of 5-(chloromethyl)-3-(4-chlorophenyl)-isoxazole (11.8 g, 51.9 mmole) in DMF. The reaction mixture was stirred at room temperature for 7 hours, and then concentrated. The solid material was treated with EtOAc/H2O, and collected by filtering. The solid material was then tritrated with H2O and EtoAc, and air-dried. The solid was further purified by re-crystallization from MeOH to obtain 5-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (8.5 g, 20.1 mmole) at 46.6% yield. 1H 300 Mhz (DMSO-d6) sigma 6.03 (s, 2p); 7.12 (s, 1p); 7.25-7.35 (m, 1p); 7.44-7.53 (m, 1p); 7.55 (d, 2p); 7.88 (d, 3p); 8.11-8.18 (m, 1p); 8.24-8.29 (dd, 1p); and 9.23 (s, 1p). LC/MS data M/z=423.34, 425.22
Example 6 5-((3-(2,4-trifluoromethylphenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00290
2,4-(bis-trifluoromethyl)benzaldoxime
To aromatic aldehyde (0.021 mol) suspended in EtOH/H2O (1:2, 230 mL, 0.09 M) was added hydroxylamine hydrochloride (1.58 g, 0.023 mol) and cooled to 4° C. To this solution was added aqueous NaOH 50% w/w (4.13 mL, 0.052 mol) dropwise. After stirring for 1.5 h at room temperature, the reaction mixture was acidified with 2N aqueous HCl and extracted with CH2Cl2 (3×50 mL). The organic solution was washed with saturated aqueous NaCl and dried over sodium sulfate. Removal of solvent gave crude oxime (5.3 g, quant.) that was used directly in the next step.
2,4-(bis-trifluoromethyl)phenyl chloromethyl isoxazole
2,4-(bis-trifluoromethyl)benzaldoxime (9.75 g, 0.038 mol) was suspended in CH2Cl2 (45 mL, 0.85 M) and cooled to 4° C. Propargyl chloride (2.72 mL, 0.038 mol) was added to the reaction solution followed by dropwise addition of NaOCl (10-13% free chlorine, 37.6 mL, 0.061 mol). The reaction mixture was stirred at 4° C. for 15 min then heated to reflux for 3 h. After cooling to room temperature, the reaction was partitioned between CH2Cl2 and H2O. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, the crude product chioromethylisoxazole was purified by column chromatography on silica (10% CH2Cl2/hexanes)(6.5 g ,0.020 mol).
5-((3-(2,4trifluoromethylphenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
To imidazopyridine (14.28 g, 0.067 mol) suspended in DMF (40 mL) was added aqueous NaOH 10% w/w (32.2 mL, 0.080 mol) dropwise followed by addition of the chloromethyl isoxazole from the previous step (26.3 g, 0.080 mol) in DMF (16 mL). After stirring for 12 h at room temperature, solvents were evaporated to give crude product as a tan solid. The crude solid was triturated with H2O (7×) and crystallized (2×) from MeO/H2O (2:1) to provide pure title product.
NMR; 300 Mhz D6MSO
Chemical shift, multiplicity, # of protons:
  • 6.1, s, 2
  • 7.0, s, 1
  • 7.3, t, 2
  • 7.4-7.5, m, 1
  • 7.8-7.9, d, 1
  • 7.9-8.0, d, 1
  • 8.2-8.4, m, 4
  • 9.2, s, 1
Example 7 5-((3-(4-trifluoromethyl-2-fluorophenyl)isoxazol-5-yl)methyl)-2-2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
Isoxazole synthesis
Figure US08329727-20121211-C00291
Figure US08329727-20121211-C00292
Compound MW Amount Moles Equivalents
A 207.13 9.3 g 0.044 1
NaOCl (10% free 74.44 43.0 mL 0.44 1.6
Cl)
Propargyl chloride 74.51 3.14 mL 0.044 1
Dichloromethane 48.7 mL
“A” was suspended in dichloromethane at 0° C. and NaOCl was added at 0° C. with vigorous stirring, followed bt propargyl chloride. Reaction stirred at 0° C. for 5 min and then heated to reflux for 2 h. It was then cooled to room temperature, washed with water, dried over sodium sulfate and concentrated in vacuo to obtain a yellow solid. It was purified on the combiflash on a silica gel column, eluting with 3-50% ethyl acetate-hexanes. 4.5 g of shiny white solid obtained.
Figure US08329727-20121211-C00293
Figure US08329727-20121211-C00294
Compound MW Amount mMoles Equivalents
A 279.62 2.0 g 7.6 1.2
B 213.21 1.373 g 6.4 1
10% w/v aq 2.26 mL
NaOH
DMF 13.73 mL +
6.56 mL
“B” was susended in 13.73 mL DMF and 10% (w/v) aq. NaOH was to it. “A” was dissolved in 6.56 mL DMF and this solution was added to the above with stirring. The reaction was stirred at room temperture for 5 hours. DMF was removed by concentrating in vacuo and the solid obtained was triturated with water two times and then with ethyl acetate. The solid thus obtained was recrystallized from methanol-water to obtain 533 mg of the desired compound.
NMR (DMSO) Data:
Chemical shift, multiplicity, # of protons:
  • 6.14, s, 2
  • 7.18, d, 1
  • 7.28-7.36, m, 2
  • 7.44-7.54, m, 1
  • 7.70-7.76, d, 1
  • 7.86-7.90, d, 1
  • 7.90-7.96, d, 1
  • 8.08-8.16, t, 1
  • 8.28-8.36, t, 2
  • 9.24, s, 1
Example 8A 5-((3-(2-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
Figure US08329727-20121211-C00295
To a solution of azabenzimidazole (12.7 g, 59.6 mmole) in DMF (120 mL) was added 10% (w/v) aqueous NaOH (30.5 mL, 76.6 mmole) followed by a solution of 5-(chloromethyl)-3-(2-trifluoromethyl-4-fluorophenyl)-isoxazole (21.3 g, 76.6 mmole) in DMF (60 mL). The reaction mixture was stirred at room temperature for 18 hours, and then concentrated. The material was precipitated from MeOH/H2O, and collected by filtering. The solid material was recrystallized from EtoAc/hexanes to obtain 5-((3-(2-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine in 69% yield.
NMR Data
300 Mhz D6MSO
Chemical shift, multiplicity, # of protons:
  • 6.15, s, 2
  • 6.91, s, 1
  • 7.3, t, 2
  • 7.42-7.52, m, 1
  • 7.65-7.9, m, 2
  • 7.84-7.9, m, 2
  • 8.22-8.45, m, 2
  • 9.19, s, 1
Example 8B Salts of 5-((3-(2-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine
Methanesulfonic Acid Salt
5-((3-(2-trifluoromethyl-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine free base (200 mg) was slurried in 2.0 mL acetone. Metlhanesulfonic acid (42.6 mg) was added and the mixture was warmed to ˜60° C. Water was added in small increments until a solution was formed (110 μL required). The solution was cooled to ambient temperature and stirred overnight. The slurry was cooled in an ice bath before being filtered and washed with acetone. The solid obtained was dried at 40° C. to give 149 mg of the desired salt. DSC endotherm 213.1° C. NMR was consistent with the desired structure.
HCl Salt
5-((3-(2-trifluoromethy-4-fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine free base (200 mg) was slurried in 2.0 mL acetone. Concentrated hydrochloric acid (46 mg) was added and the mixture was warmed to ˜60° C. Water was added to the thick slurry in small increments until a solution was formed (100 μL required). The solution was cooled to ambient temperature and stirred overnight. The slurry was cooled in an ice bath before being filtered and washed with acetone. The solid obtained was dried at 40° C. to give 80 mg of the desired salt. DSC endotherm 241.5° C. NMR consistent with the desired structure.
Example 8B Formulation of 5-((3-(2-trifluoromethy-4fluorophenyl)isoxazol-5-yl)methyl)-2-(2-fluorophenyl)-5H-imidazo[4,5-c]pyridine salts
Either salt of Example 7B was mixed 1:1 by weight in dry pregelatized starch. 100 mg of the mixture was loaded into a hard gel capsule.
Additional compounds of this invention were made by the methods of procedures A, C, D, E and F.
Procedure A; Alkylation
Figure US08329727-20121211-C00296
For compounds prepared in an array format, 100 um of the scaffold (in this case 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine) was used for each reaction. The total amount of 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine was dissolved in enough DMF to give 500 ul/reaction. To each solution was added 60 μL of 10%(w/v)NaOH/H2O. The alkylating agents were dissolved in DMF at a concentration 480 μmole/mL and 250 μL of these solutions were added to the respective reaction. Each reaction was then heated to 110° C. for 1 min using microwave irradiation. After cooling, the reactions were filtered through a 0.45 um filter. Each compound was then purified by mass based fractionation on a C-18 reverse phase column using 0.1%TFA/ H2O and 0.1%TFA/Acetonitrfle as the eluting solvents. Each compound was identified by its mass spectrum and purity was determined by UV absorbance at 254 mn. The BLC fractions were concentrated by centrifugal evaporation and weighed to determine quantity collected.
Procedure C. Suzuki Boronic Acid
Figure US08329727-20121211-C00297
The aryl boronic acid (1.2 eq.) was added to a solution of 5-(4-iodobenzyl)-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine (1 eq.) in DMF. Na2CO3 (2 eq) was dissolved in H2O, added to the DMF solution and stirred. Pd(PPh3)4 (5 mole %) was then added to the DMF reaction mixture. The reaction mixture was heated in a microwave at 200° C. for 2 minutes. The reaction mixture was applied to a 1 g solid phase extraction cartridge (C-18) and the column was washed with 3×2 mL of methanol. The eluents were filtered through a 0.45 um filter and then concentrated to dryness. The resulting material was redissolved in DMF, and purified by reverse phase HPLC/MS.
Procedure D
General Procedure for Oxime Formation
To aromatic aldehyde suspended in EtOH/H2O (1:2) was added hydroxylamine hydrochloride (1.1 equiv.) and cooled to 4° C. To this solution was added aqueous NaOH 50% w/w (2.5 equiv.) dropwise. After stirring for 1.5 h at room temperature, the reaction mixture was acidified with 2N aqueous HCl and extracted with CH2Cl2. The organic solution was washed with saturated aqueous NaCl and dried over sodium sulfate. Removal of solvent gave crude oxime that was used directly in the next step.
General Procedure for Cycloaddition
Oxime was suspended in CH2Cl2 and cooled to 4° C. Propargyl chloride (1 equiv.) was added to the reaction solution followed by dropwise addition of NaOCl (10-13% free chlorine, 1 equiv.). The reaction mixture was stirred at 4° C. for 15 min then heated to reflux for 3 h. After cooling to room temperature, the reaction was partitioned between CH2Cl2 and H2O. The organic layer was separated, washed with saturated aqueous NaCl, and dried over sodium sulfate. After removal of solvent, the crude product was purified by trituration (hexanes ) or by column chromatography on silica (10% CH2Cl2/hexanes).
General Procedure for Alkylation
To imidazopyridine suspended in DMF was added aqueous NaOH 10% w/w (1.2 equiv.) dropwise followed by addition of chloromethyl isoxazole (1.2 equiv.) in DNF. After stirring for 12 h at room temperature, solvents were evaporated to give crude product as a tan solid. The crude solid was triturated with H2O and crystallized from MeOH/H2O (2:1) to provide pure final product.
Procedure E: Suzuki Bromides
Figure US08329727-20121211-C00298
The aryl bromide (1.2 eq.) was added to a solution of 4-((2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridin-5-yl)methyl)phenylboronic acid (1 eq.) in DMF. Na2CO3 (2 eq) was dissolved in H2O, added to the DMF solution and stirred. Pd(PPh3)4 (5 mole %) was then added to the DMF reaction mixture. The reaction mixture was heated in a microwave at 200° C. for 2 minutes. The reaction mixture was applied to a 1 g solid phase extraction cartridge (C-18) and the column was washed with 3×2 mL of methanol. The eluents were filtered through a 0.45 um filter and then concentrated to dryness. The resulting material was redissolved in DMF, and purified by reverse phase HPLC/MS.
Procedure F
Preparation of Biphenyl Array
Figure US08329727-20121211-C00299
The appropriately substituted 4′-[2-(2,3-Difluoro-phenyl)-imidazo[4,5-c]pyridin-5-ylmethyl]-biphenyl4-ol (5) scaffold was prepared by first treating 2-(2,3-Difluoro-phenyl)-3H-imidazo[4,5-c]pyridine) (1) with 1-bromomethyl-4-iodobenzene (2) in DMF using aqueous sodium hydroxide as base. The resulting 2-(2,3-Difluoro-phenyl)-5-(4-iodo-benzyl)-5H-imidazo[4,5-c]pyridine (3) (1 equivalent) was treated with three different substituted 4-hydroxyphenyl boronic acids ((4-hydroxyphenyl)boronic acid, 4-Hydroxy-2-(trifluoromethyl)phenyl boronic acid and (4-hydroxy-2-methylphenyl)boronic acid) and (4-Fluoro-2-hydroxy)phenylboronic acid (1.1 equivalents) under Suzuki coupling conditions (sodium carbonate, water, palladium tetrakis(triphenyl)phosphine) to afford the appropriately substituted 4′-[2-(2,3-Difluoro-phenyl)-imidazo[4,5-c]pyridin-5-ylmethyl]-biphenylsol or -[2-(2,3-Difluoro-phenyl)-imidazo[4,5-c]pyridin-5-ylmethyl]-biphenyl-2-ol. The products were precipitated in ethyl acetate and filtered over a medium frit followed by washing with water to afford the pure product (5).
For compounds prepared in array format of the general type (7), 50 μM of the scaffold (5) in 250 μL DMF was used for each reaction. To each reaction was added 1.4 equivalents of Cesium Carbonate. The alkylating agents (6) were added as a 0.4M solution (0.05 mMoles) in DMF. The reactions were shaken at 60° C. for 4 hours and monitored by analytical LC/MS. Each reaction was filtered through a 0.45 μM filter and purified by mass-based fractionation on a C-18 reverse phase column using 0.1%TFA/water and 0.1%TFA/acetonitrile as the eluting solvents. Each compound was identified by its mass spectrum and purity was determined by its UV absorbance at 254 nm. The HPLC fractions were concentrated in vacuo and weighed to afford the product (7) as its trifluoroacetate salt.
The compounds produced according to these procedures and examples, and certain of their properties, are described in the Table below. The substituent designated “C” is methyl.
Structures Purity MW Obs. MW Method
Example 9
Figure US08329727-20121211-C00300
 		95 387.340 388.340 A
Example 10
Figure US08329727-20121211-C00301
 		90 395.440 396.440 A
Example 11
Figure US08329727-20121211-C00302
 		90 413.431 414.431 A
Example 12
Figure US08329727-20121211-C00303
 		92 404.451 405.541 A
Example 13
Figure US08329727-20121211-C00304
 		95 407.451 408.451 A
Example 14
Figure US08329727-20121211-C00305
 		85 405.479 406.479 A
Example 15
Figure US08329727-20121211-C00306
 		90 389.331 390.331 A
Example 16
Figure US08329727-20121211-C00307
 		90 431.418 432.418 A
Example 17
Figure US08329727-20121211-C00308
 		93 404.834 405.834 A
Example 18
Figure US08329727-20121211-C00309
 		90 370.389 371.389 A
Example 19
Figure US08329727-20121211-C00310
 		95 389.331 390.331 A
Example 20
Figure US08329727-20121211-C00311
 		95 389.331 390.331 A
Example 21
Figure US08329727-20121211-C00312
 		95 389.331 390.331 A
Example 22
Figure US08329727-20121211-C00313
 		97 355.777 356.777 A
Example 23
Figure US08329727-20121211-C00314
 		90 407.451 408.451 A
Example 24
Figure US08329727-20121211-C00315
 		90 461.134 462.134 A
Example 25
Figure US08329727-20121211-C00316
 		90 401.404 402.404 A
Example 26
Figure US08329727-20121211-C00317
 		95 371.377 372.377 A
Example 27
Figure US08329727-20121211-C00318
 		95 439.375 440.375 A
Example 28
Figure US08329727-20121211-C00319
 		90 405.822 406.822 A
Example 29
Figure US08329727-20121211-C00320
 		90 427.485 428.485 A
Example 30
Figure US08329727-20121211-C00321
 		85 456.833 457.833 A
Example 31
Figure US08329727-20121211-C00322
 		95 439.375 440.375 A
Example 32
Figure US08329727-20121211-C00323
 		90 386.454 387.454 A
Example 33
Figure US08329727-20121211-C00324
 		90 392.480 393.480 A
Example 34
Figure US08329727-20121211-C00325
 		95 361.301 362.301 A
Example 35
Figure US08329727-20121211-C00326
 		92 369.804 370.804 A
Example 36
Figure US08329727-20121211-C00327
 		90 405.785 406.785 A
Example 37
Figure US08329727-20121211-C00328
 		92 421.785 422.785 A
Example 38
Figure US08329727-20121211-C00329
 		90 401.367 402.367 A
Example 39
Figure US08329727-20121211-C00330
 		90 351.814 352.814 A
Example 40
Figure US08329727-20121211-C00331
 		92 423.812 424.812 A
Example 41
Figure US08329727-20121211-C00332
 		98 339.391 340.391 A
Example 42
Figure US08329727-20121211-C00333
 		92 449.408 450.408 A
Example 43
Figure US08329727-20121211-C00334
 		95 422.825 423.825 A
Example 44
Figure US08329727-20121211-C00335
 		93 388.380 389.380 A
Example 45
Figure US08329727-20121211-C00336
 		95 479.124 480.124 A
Example 46
Figure US08329727-20121211-C00337
 		97 419.394 420.394 A
Example 47
Figure US08329727-20121211-C00338
 		94 389.367 390.367 A
Example 48
Figure US08329727-20121211-C00339
 		92 457.366 458.366 A
Example 49
Figure US08329727-20121211-C00340
 		90 363.778 364.778 A
Example 50
Figure US08329727-20121211-C00341
 		92 445.476 446.476 A
Example 51
Figure US08329727-20121211-C00342
 		95 457.366 458.366 A
Example 52
Figure US08329727-20121211-C00343
 		95 472.443 473.443 A
Example 53
Figure US08329727-20121211-C00344
 		95 404.444 405.444 A
Example 54
Figure US08329727-20121211-C00345
 		95 395.393 396.393 A
Example 55
Figure US08329727-20121211-C00346
 		90 410.470 411.470 A
Example 56
Figure US08329727-20121211-C00347
 		92 457.329 458.329 A
Example 57
Figure US08329727-20121211-C00348
 		93 353.350 354.350 A
Example 58
Figure US08329727-20121211-C00349
 		95 423.776 424.776 A
Example 59
Figure US08329727-20121211-C00350
 		95 439.775 440.775 A
Example 60
Figure US08329727-20121211-C00351
 		92 419.357 420.357 A
Example 61
Figure US08329727-20121211-C00352
 		90 390.222 391.222 A
Example 62
Figure US08329727-20121211-C00353
 		90 405.330 406.330 A
Example 63
Figure US08329727-20121211-C00354
 		90 431.421 432.421 A
Example 64
Figure US08329727-20121211-C00355
 		0 422.441 423.441 A
Example 65
Figure US08329727-20121211-C00356
 		90 425.442 426.442 A
Example 66
Figure US08329727-20121211-C00357
 		95 431.786 432.876 C
Example 67
Figure US08329727-20121211-C00358
 		95 442.429 443.429 C
Example 68
Figure US08329727-20121211-C00359
 		95 411.458 412.458 C
Example 69
Figure US08329727-20121211-C00360
 		95 411.458 412.458 C
Example 70
Figure US08329727-20121211-C00361
 		95 411.458 412.458 C
Example 71
Figure US08329727-20121211-C00362
 		95 415.422 416.422 C
Example 72
Figure US08329727-20121211-C00363
 		95 403.457 404.457 C
Example 73
Figure US08329727-20121211-C00364
 		90 441.485 442.485 C
Example 74
Figure US08329727-20121211-C00365
 		95 465.430 466.430 C
Example 75
Figure US08329727-20121211-C00366
 		95 431.876 432.876 C
Example 76
Figure US08329727-20121211-C00367
 		95 415.422 416.422 C
Example 77
Figure US08329727-20121211-C00368
 		95 441.485 442.485 C
Example 78
Figure US08329727-20121211-C00369
 		95 441.485 442.485 C
Example 79
Figure US08329727-20121211-C00370
 		95 443.522 444.522 C
Example 80
Figure US08329727-20121211-C00371
 		95 387.392 388.392 C
Example 81
Figure US08329727-20121211-C00372
 		95 433.412 434.412 C
Example 82
Figure US08329727-20121211-C00373
 		95 439.469 440.469 C
Example 83
Figure US08329727-20121211-C00374
 		95 439.469 440.469 C
Example 84
Figure US08329727-20121211-C00375
 		95 425.485 426.485 C
Example 85
Figure US08329727-20121211-C00376
 		95 465.430 466.430 C
Example 86
Figure US08329727-20121211-C00377
 		95 465.430 466.430 C
Example 87
Figure US08329727-20121211-C00378
 		95 415.422 416.422 C
Example 88
Figure US08329727-20121211-C00379
 		95 466.321 467.321 C
Example 89
Figure US08329727-20121211-C00380
 		95 433.412 434.412 C
Example 90
Figure US08329727-20121211-C00381
 		95 533.428 534.428 C
Example 91
Figure US08329727-20121211-C00382
 		95 466.321 467.321 C
Example 92
Figure US08329727-20121211-C00383
 		90 425.485 426.485 C
Example 93
Figure US08329727-20121211-C00384
 		90 457.484 458.454 C
Example 94
Figure US08329727-20121211-C00385
 		90 447.492 448.492 C
Example 95
Figure US08329727-20121211-C00386
 		90 489.529 490.529 C
Example 96
Figure US08329727-20121211-C00387
 		90 457.484 458.484 C
Example 97
Figure US08329727-20121211-C00388
 		90 425.485 426.485 C
Example 98
Figure US08329727-20121211-C00389
 		90 425.485 426.485 C
Example 99
Figure US08329727-20121211-C00390
 		90 440.500 441.500 C
Example 100
Figure US08329727-20121211-C00391
 		90 429.449 430.449 C
Example 101
Figure US08329727-20121211-C00392
 		90 437.902 438.902 C
Example 102
Figure US08329727-20121211-C00393
 		90 437.453 438.453 C
Example 103
Figure US08329727-20121211-C00394
 		90 453.517 454.517 C
Example 104
Figure US08329727-20121211-C00395
 		90 481.429 482.429 C
Example 105
Figure US08329727-20121211-C00396
 		90 481.429 482.429 C
Example 106
Figure US08329727-20121211-C00397
 		90 453.517 454.517 C
Example 107
Figure US08329727-20121211-C00398
 		90 449.867 450.867 C
Example 108
Figure US08329727-20121211-C00399
 		90 466.321 467.321 C
Example 109
Figure US08329727-20121211-C00400
 		90 422.441 423.441 C
Example 110
Figure US08329727-20121211-C00401
 		90 433.412 434.412 C
Example 111
Figure US08329727-20121211-C00402
 		90 442.429 443.429 C
Example 112
Figure US08329727-20121211-C00403
 		90 427.458 428.458 C
Example 113
Figure US08329727-20121211-C00404
 		90 427.458 428.458 C
Example 114
Figure US08329727-20121211-C00405
 		90 425.485 426.485 C
Example 115
Figure US08329727-20121211-C00406
 		90 439.512 440.512 C
Example 116
Figure US08329727-20121211-C00407
 		90 466.321 467.321 C
Example 117
Figure US08329727-20121211-C00408
 		90 503.556 504.556 C
Example 118
Figure US08329727-20121211-C00409
 		90 443.522 444.522 C
Example 119
Figure US08329727-20121211-C00410
 		90 422.441 423.441 C
Example 120
Figure US08329727-20121211-C00411
 		90 475.521 476.521 C
Example 121
Figure US08329727-20121211-C00412
 		90 433.412 434.412 C
Example 122
Figure US08329727-20121211-C00413
 		90 503.556 504.556 C
Example 123
Figure US08329727-20121211-C00414
 		90 429.449 430.449 C
Example 124
Figure US08329727-20121211-C00415
 		90 453.540 454.540 C
Example 125
Figure US08329727-20121211-C00416
 		90 466.321 467.321 C
Example 126
Figure US08329727-20121211-C00417
 		90 456.456 457.456 C
Example 127
Figure US08329727-20121211-C00418
 		90 481.429 482.429 C
Example 128
Figure US08329727-20121211-C00419
 		90 483.522 484.522 C
Example 129
Figure US08329727-20121211-C00420
 		90 445.448 446.448 C
Example 130
Figure US08329727-20121211-C00421
 		90 392.870 393.870 A
Example 131
Figure US08329727-20121211-C00422
 		90 358.425 359.425 A
Example 132
Figure US08329727-20121211-C00423
 		90 392.486 393.486 A
Example 133
Figure US08329727-20121211-C00424
 		90 453.540 454.540 C
Example 134
Figure US08329727-20121211-C00425
 		90 546.582 547.582 C
Example 135
Figure US08329727-20121211-C00426
 		90 445.448 446.448 C
Example 136
Figure US08329727-20121211-C00427
 		0 456.378 457.378 A
Example 137
Figure US08329727-20121211-C00428
 		95 472.378 473.378 A
Example 138
Figure US08329727-20121211-C00429
 		95 423.812 424.812 A
Example 139
Figure US08329727-20121211-C00430
 		99 457.270 458.270 D
Example 140
Figure US08329727-20121211-C00431
 		98 472.378 473.378 D
Example 141
Figure US08329727-20121211-C00432
 		98 524.377 525.377 D
Example 142
Figure US08329727-20121211-C00433
 		0 474.369 475.369 D
Example 143
Figure US08329727-20121211-C00434
 		99 454.387 455.387 D
Example 144
Figure US08329727-20121211-C00435
 		98 474.369 475.369 D
Example 145
Figure US08329727-20121211-C00436
 		98 485.266 486.266 D
Example 146
Figure US08329727-20121211-C00437
 		95 442.351 443.351 D
Example 147
Figure US08329727-20121211-C00438
 		90 420.397 421.397 D
Example 148
Figure US08329727-20121211-C00439
 		90 402.407 403.407 D
Example 149
Figure US08329727-20121211-C00440
 		98 448.433 449.433 D
Example 150
Figure US08329727-20121211-C00441
 		98 474.369 475.369 D
Example 151
Figure US08329727-20121211-C00442
 		96 439.280 440.280 D
Example 152
Figure US08329727-20121211-C00443
 		98 454.387 455.387 D
Example 153
Figure US08329727-20121211-C00444
 		98 506.386 507.386 D
Example 154
Figure US08329727-20121211-C00445
 		98 456.378 457.378 D
Example 155
Figure US08329727-20121211-C00446
 		98 436.397 437.397 D
Example 156
Figure US08329727-20121211-C00447
 		98 456.378 457.378 D
Example 157
Figure US08329727-20121211-C00448
 		98 467.276 468.276 D
Example 158
Figure US08329727-20121211-C00449
 		98 430.442 431.442 D
Example 159
Figure US08329727-20121211-C00450
 		98 456.378 457.378 D
Example 160
Figure US08329727-20121211-C00451
 		85 473.725 474.725 D
Example 161
Figure US08329727-20121211-C00452
 		98 488.832 489.832 D
Example 162
Figure US08329727-20121211-C00453
 		98 540.831 541.831 D
Example 163
Figure US08329727-20121211-C00454
 		98 490.823 491.823 D
Example 164
Figure US08329727-20121211-C00455
 		98 470.842 471.842 D
Example 165
Figure US08329727-20121211-C00456
 		98 490.823 491.823 D
Example 166
Figure US08329727-20121211-C00457
 		98 501.721 502.721 D
Example 167
Figure US08329727-20121211-C00458
 		90 415.422 416.422 C
Example 168
Figure US08329727-20121211-C00459
 		90 483.420 484.420 C
Example 169
Figure US08329727-20121211-C00460
 		90 499.419 500.419 C
Example 170
Figure US08329727-20121211-C00461
 		90 445.448 446.448 C
Example 171
Figure US08329727-20121211-C00462
 		90 461.513 462.513 C
Example 172
Figure US08329727-20121211-C00463
 		90 451.402 452.402 C
Example 173
Figure US08329727-20121211-C00464
 		90 465.430 466.430 C
Example 174
Figure US08329727-20121211-C00465
 		90 481.429 482.429 C
Example 175
Figure US08329727-20121211-C00466
 		90 427.458 428.458 C
Example 176
Figure US08329727-20121211-C00467
 		90 443.522 444.522 C
Example 177
Figure US08329727-20121211-C00468
 		90 433.412 434.412 C
Example 178
Figure US08329727-20121211-C00469
 		90 431.876 432.876 C
Example 179
Figure US08329727-20121211-C00470
 		90 515.874 516.874 C
Example 180
Figure US08329727-20121211-C00471
 		90 461.903 462.903 C
Example 181
Figure US08329727-20121211-C00472
 		90 477.967 478.967 C
Example 182
Figure US08329727-20121211-C00473
 		90 467.857 468.857 C
Example 183
Figure US08329727-20121211-C00474
 		90 501.410 502.410 C
Example 184
Figure US08329727-20121211-C00475
 		90 397.431 398.431 C
Example 185
Figure US08329727-20121211-C00476
 		95 479.556 480.556 E
Example 186
Figure US08329727-20121211-C00477
 		95 423.469 424.469 E
Example 187
Figure US08329727-20121211-C00478
 		95 441.485 442.485 E
Example 188
Figure US08329727-20121211-C00479
 		95 455.468 456.468 E
Example 189
Figure US08329727-20121211-C00480
 		95 469.495 470.495 E
Example 190
Figure US08329727-20121211-C00481
 		95 483.522 484.522 E
Example 192
Figure US08329727-20121211-C00482
 		95 436.468 437.468 E
Example 193
Figure US08329727-20121211-C00483
 		95 475.475 476.475 E
Example 194
Figure US08329727-20121211-C00484
 		95 453.496 454.496 E
Example 195
Figure US08329727-20121211-C00485
 		95 463.438 464.438 E
Example 196
Figure US08329727-20121211-C00486
 		95 464.479 465.479 E
Example 199
Figure US08329727-20121211-C00487
 		90 415.422 416.422 C
Example 200
Figure US08329727-20121211-C00488
 		90 483.420 484.420 C
Example 201
Figure US08329727-20121211-C00489
 		90 499.419 500.419 C
Example 202
Figure US08329727-20121211-C00490
 		90 445.448 446.448 C
Example 203
Figure US08329727-20121211-C00491
 		90 461.513 462.513 C
Example 204
Figure US08329727-20121211-C00492
 		90 451.402 452.402 C
Example 205
Figure US08329727-20121211-C00493
 		90 397.431 398.431 C
Example 206
Figure US08329727-20121211-C00494
 		90 465.430 466.430 C
Example 207
Figure US08329727-20121211-C00495
 		90 481.429 482.429 C
Example 208
Figure US08329727-20121211-C00496
 		90 427.458 428.458 C
Example 209
Figure US08329727-20121211-C00497
 		90 443.522 444.522 C
Example 210
Figure US08329727-20121211-C00498
 		90 433.412 434.412 C
Example 211
Figure US08329727-20121211-C00499
 		90 431.876 432.876 C
Example 212
Figure US08329727-20121211-C00500
 		90 499.875 500.875 C
Example 213
Figure US08329727-20121211-C00501
 		90 477.967 478.967 C
Example 214
Figure US08329727-20121211-C00502
 		95 462.506 463.506 E
Example 215
Figure US08329727-20121211-C00503
 		95 421.840 422.840 A
Example 216
Figure US08329727-20121211-C00504
 		95 403.850 404.850 A
Example 217
Figure US08329727-20121211-C00505
 		95 417.422 418.422 A
Example 218
Figure US08329727-20121211-C00506
 		95 399.431 400.431 A
Example 219
Figure US08329727-20121211-C00507
 		95 434.400 435.400 A
Example 220
Figure US08329727-20121211-C00508
 		95 416.409 417.409 A
Example 221
Figure US08329727-20121211-C00509
 		98 424.361 425.361 D
Example 222
Figure US08329727-20121211-C00510
 		85 406.370 407.370 D
Example 223
Figure US08329727-20121211-C00511
 		98 440.815 441.815 D
Example 224
Figure US08329727-20121211-C00512
 		90 553.493 554.493 F
Example 225
Figure US08329727-20121211-C00513
 		90 567.520 568.520 F
Example 226
Figure US08329727-20121211-C00514
 		90 579.575 580.575 F
Example 227
Figure US08329727-20121211-C00515
 		84 551.521 552.521 F
Example 228
Figure US08329727-20121211-C00516
 		100 537.537 538.537 F
Example 229
Figure US08329727-20121211-C00517
 		92 551.564 552.564 F
Example 230
Figure US08329727-20121211-C00518
 		100 593.646 594.646 F
Example 231
Figure US08329727-20121211-C00519
 		81 567.520 568.520 F
Example 232
Figure US08329727-20121211-C00520
 		78 539.510 540.510 F
Example 233
Figure US08329727-20121211-C00521
 		77 583.563 584.563 F
Example 234
Figure US08329727-20121211-C00522
 		85 549.548 550.548 F
Example 235
Figure US08329727-20121211-C00523
 		85 579.531 580.531 F
Example 236
Figure US08329727-20121211-C00524
 		82 593.558 594.558 F
Example 237
Figure US08329727-20121211-C00525
 		90 535.521 536.521 F
Example 238
Figure US08329727-20121211-C00526
 		85 551.564 552.564 F
Example 239
Figure US08329727-20121211-C00527
 		85 595.574 596.574 F
Example 240
Figure US08329727-20121211-C00528
 		80 551.564 552.564 F
Example 241
Figure US08329727-20121211-C00529
 		85 535.521 536.521 F
Example 242
Figure US08329727-20121211-C00530
 		85 577.603 578.603 F
Example 243
Figure US08329727-20121211-C00531
 		100 595.574 596.574 F
Example 244
Figure US08329727-20121211-C00532
 		83 533.505 534.505 F
Example 245
Figure US08329727-20121211-C00533
 		90 487.529 488.529 F
Example 246
Figure US08329727-20121211-C00534
 		90 501.556 502.556 F
Example 247
Figure US08329727-20121211-C00535
 		90 501.556 502.556 F
Example 248
Figure US08329727-20121211-C00536
 		90 501.556 502.556 F
Example 249
Figure US08329727-20121211-C00537
 		90 539.485 540.485 F
Example 250
Figure US08329727-20121211-C00538
 		90 483.497 484.497 F
Example 251
Figure US08329727-20121211-C00539
 		90 483.566 484.566 F
Example 252
Figure US08329727-20121211-C00540
 		90 513.549 514.549 F
Example 253
Figure US08329727-20121211-C00541
 		90 485.538 486.538 F
Example 254
Figure US08329727-20121211-C00542
 		90 529.592 530.592 F
Example 255
Figure US08329727-20121211-C00543
 		90 525.560 526.560 F
Example 256
Figure US08329727-20121211-C00544
 		90 481.550 482.550 F
Example 257
Figure US08329727-20121211-C00545
 		90 541.603 542.603 F
Example 258
Figure US08329727-20121211-C00546
 		90 481.550 482.550 F
Example 259
Figure US08329727-20121211-C00547
 		90 541.603 542.603 F
Example 260
Figure US08329727-20121211-C00548
 		90 479.534 480.534 F
Example 261
Figure US08329727-20121211-C00549
 		90 522.559 523.559 F
Example 262
Figure US08329727-20121211-C00550
 		90 469.539 470.539 F
Example 263
Figure US08329727-20121211-C00551
 		90 471.511 472.511 F
Example 264
Figure US08329727-20121211-C00552
 		90 515.565 516.565 F
Example 265
Figure US08329727-20121211-C00553
 		90 511.533 512.533 F
Example 266
Figure US08329727-20121211-C00554
 		90 467.523 468.523 F
Example 267
Figure US08329727-20121211-C00555
 		90 527.576 528.576 F
Example 268
Figure US08329727-20121211-C00556
 		90 521.494 522.494 F
Example 269
Figure US08329727-20121211-C00557
 		80 465.507 466.507 F
Example 270
Figure US08329727-20121211-C00558
 		90 453.496 454.496 F
Example 271
Figure US08329727-20121211-C00559
 		90 470.483 471.483 F
Example 272
Figure US08329727-20121211-C00560
 		90 495.577 496.577 F
Example 273
Figure US08329727-20121211-C00561
 		90 481.550 482.550 F
Example 274
Figure US08329727-20121211-C00562
 		90 610.644 611.644 F
Example 275
Figure US08329727-20121211-C00563
 		90 506.560 507.560 F
Example 276
Figure US08329727-20121211-C00564
 		90 485.538 486.538 F
Example 277
Figure US08329727-20121211-C00565
 		90 595.574 596.574 F
Example 278
Figure US08329727-20121211-C00566
 		90 521.494 522.494 F
Example 279
Figure US08329727-20121211-C00567
 		90 538.481 539.481 F
Example 280
Figure US08329727-20121211-C00568
 		90 563.576 564.576 F
Example 281
Figure US08329727-20121211-C00569
 		85 565.548 566.548 F
Example 282
Figure US08329727-20121211-C00570
 		90 580.606 581.606 F
Example 283
Figure US08329727-20121211-C00571
 		90 549.548 550.548 F
Example 284
Figure US08329727-20121211-C00572
 		85 678.643 679.643 F
Example 285
Figure US08329727-20121211-C00573
 		90 574.558 575.558 F
Example 286
Figure US08329727-20121211-C00574
 		90 588.585 589.585 F
Example 287
Figure US08329727-20121211-C00575
 		90 659.599 660.599 F
Example 288
Figure US08329727-20121211-C00576
 		90 617.547 618.547 F
Example 289
Figure US08329727-20121211-C00577
 		90 572.542 573.542 F
Example 290
Figure US08329727-20121211-C00578
 		90 553.537 554.537 F
Example 291
Figure US08329727-20121211-C00579
 		90 629.514 630.514 F
Example 292
Figure US08329727-20121211-C00580
 		85 571.502 572.502 F
Example 293
Figure US08329727-20121211-C00581
 		80 545.566 546.566 F
Example 294
Figure US08329727-20121211-C00582
 		90 471.486 472.486 F
Example 295
Figure US08329727-20121211-C00583
 		90 488.473 489.473 F
Example 296
Figure US08329727-20121211-C00584
 		90 628.635 629.635 F
Example 297
Figure US08329727-20121211-C00585
 		90 524.550 525.550 F
Example 298
Figure US08329727-20121211-C00586
 		90 538.577 539.577 F
Example 300
Figure US08329727-20121211-C00587
 		90 503.529 504.529 F
Example 301
Figure US08329727-20121211-C00588
 		90 579.506 580.506 F
Example 302
Figure US08329727-20121211-C00589
 		90 521.494 522.494 F
Example 303
Figure US08329727-20121211-C00590
 		90 541.603 542.603 F
Example 304
Figure US08329727-20121211-C00591
 		90 467.523 468.523 F
Example 305
Figure US08329727-20121211-C00592
 		90 483.566 484.566 F
Example 306
Figure US08329727-20121211-C00593
 		90 509.604 510.604 F
Example 307
Figure US08329727-20121211-C00594
 		90 511.577 512.577 F
Example 308
Figure US08329727-20121211-C00595
 		90 495.577 496.577 F
Example 309
Figure US08329727-20121211-C00596
 		90 520.587 521.587 F
Example 310
Figure US08329727-20121211-C00597
 		90 534.614 535.614 F
Example 311
Figure US08329727-20121211-C00598
 		90 605.627 606.627 F
Example 312
Figure US08329727-20121211-C00599
 		90 563.576 564.576 F
Example 313
Figure US08329727-20121211-C00600
 		90 499.565 500.565 F
Example 314
Figure US08329727-20121211-C00601
 		90 575.543 576.543 F
Example 315
Figure US08329727-20121211-C00602
 		90 791.891 792.891 F
Example 316
Figure US08329727-20121211-C00603
 		95 486.405 487.405 D
Example 317
Figure US08329727-20121211-C00604
 		90 417.397 418.397 A
Example 318
Figure US08329727-20121211-C00605
 		90 396.787 397.787 A
Example 319
Figure US08329727-20121211-C00606
 		90 387.34 A
Example 320
Figure US08329727-20121211-C00607
 		90 371.34 A
Example 321
Figure US08329727-20121211-C00608
 		90 400.23 A
Example 322
Figure US08329727-20121211-C00609
 		90 401.37 A
Example 323
Figure US08329727-20121211-C00610
 		90 405.33 A
Example 324
Figure US08329727-20121211-C00611
 		90 345.42 A
Example 325
Figure US08329727-20121211-C00612
 		90 409.47 A
Example 326
Figure US08329727-20121211-C00613
 		90 403.40 A
Example 327
Figure US08329727-20121211-C00614
 		90 363.41 A
Example 328
Figure US08329727-20121211-C00615
 		90 389.33 A
Example 329
Figure US08329727-20121211-C00616
 		90 359.45 A
Example 330
Figure US08329727-20121211-C00617
 		90 385.37 A
Example 331
Figure US08329727-20121211-C00618
 		90 417.37 A
Example 332
Figure US08329727-20121211-C00619
 		90 421.78 A
Example 333
Figure US08329727-20121211-C00620
 		90 466.24 A
Example 334
Figure US08329727-20121211-C00621
 		90 393.90 A
Example 335
Figure US08329727-20121211-C00622
 		90 416.68 A
Example 336
Figure US08329727-20121211-C00623
 		90 405.79 A
Example 337
Figure US08329727-20121211-C00624
 		90 463.68 A
Example 338
Figure US08329727-20121211-C00625
 		90 379.87 A
Example 339
Figure US08329727-20121211-C00626
 		90 423.81
Example 340
Figure US08329727-20121211-C00627
 		90 419.39
Example 341
Figure US08329727-20121211-C00628
 		90 403.39
Example 342
Figure US08329727-20121211-C00629
 		90 418.41 D
Example 343
Figure US08329727-20121211-C00630
 		90 402.41 D
Example 344
Figure US08329727-20121211-C00631
 		90 378.34 D
Example 345
Figure US08329727-20121211-C00632
 		90 394.41 D
Example 346
Figure US08329727-20121211-C00633
 		90 431.45 D
Example 347
Figure US08329727-20121211-C00634
 		90 464.48 D
Example 348
Figure US08329727-20121211-C00635
 		90 467.28 D
Example 349
Figure US08329727-20121211-C00636
 		90 494.51 D
Example 350
Figure US08329727-20121211-C00637
 		90 434.47 D
Example 351
Figure US08329727-20121211-C00638
 		90 432.43 D
Example 352
Figure US08329727-20121211-C00639
 		90 432.43 D
Example 353
Figure US08329727-20121211-C00640
 		90 436.40 D
Example 354
Figure US08329727-20121211-C00641
 		90 440.82 D
Example 355
Figure US08329727-20121211-C00642
 		90 446.46 D
Example 356
Figure US08329727-20121211-C00643
 		90 480.48 D
Example 357
Figure US08329727-20121211-C00644
 		90 391.38 D
Example 358
Figure US08329727-20121211-C00645
 		90 446.46 D
Example 359
Figure US08329727-20121211-C00646
 		90 440.82 D
Example 360
Figure US08329727-20121211-C00647
 		90 478.48 D
Example 361
Figure US08329727-20121211-C00648
 		90 428.85 D
Example 362
Figure US08329727-20121211-C00649
 		90 460.49 D
Example 363
Figure US08329727-20121211-C00650
 		90 428.47 D
Example 364
Figure US08329727-20121211-C00651
 		90 444.44 D
Example 365
Figure US08329727-20121211-C00652
 		90 474.51 D
Example 366
Figure US08329727-20121211-C00653
 		90 473.30 D
Example 367
Figure US08329727-20121211-C00654
 		90 378.34 D
Example 368
Figure US08329727-20121211-C00655
 		90 500.55 D
Example 369
Figure US08329727-20121211-C00656
 		90 500.55 D
Example 370
Figure US08329727-20121211-C00657
 		90 488.54 D
Example 371
Figure US08329727-20121211-C00658
 		90 488.53 D
Example 372
Figure US08329727-20121211-C00659
 		90 487.4 D
Example 373
Figure US08329727-20121211-C00660
 		90 417.4 C
Example 374
Figure US08329727-20121211-C00661
To a stirred solution of 4-ethoxy-benzaldehyde (3.000 g) in 50% ethanol (7 mL) ice (10 g) and hydroxylamine hydrochloride (2.100 g) were added, followed by 30% aqueous sodium hydroxide solution (3.5 mL). After completion of the reaction (1 h) hydrochloric acid was added to adjust pH to 1 and the suspension was cooled on an ice bath and filtered. The crude oxime can be used for the next step without purification. Alternatively, it can be recrystallized from a mixture of diisopropyl ether and ethyl acetate. Yield: 71%.
To a solution of propargyl chloride (655 mg, 1 equ.) and triethylamine (35 mg, 0.1 equ.) in dicbloromethane (9.5 mL) were subsequently added with cooling 10% aqueous sodium hypochlorite solution (9.5 mL, 1.5 equ.) and then a solution of the oxime (1.40 g, ˜1.3 M in dichloromethane) over a period of 15 minutes and stirring was continued for an additional hour. The reaction was monitored by TLC (silicagel, eluent: 5% MeOH in dichloromethane). After completion the reaction mixture was extracted 3 times with 30 mL dichloromethane. The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure. The crude 5-(chloromethyl)-3-(4-ethoxyphenyl)-isoxazole was purified by column chromatography (silicagel, ethyl acetate/petroleum ether=1:9). Yield: 1.1 g.
A mixture of 3,4-diaminopyridine (2.00 g), 2,3-difluorobenzoic acid (1 equivalent) and polyphosphoric acid (50 g) was heated at 180° C. for 4 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid NaOH. The crude 2-(2,3-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine was collected by filtration, washed with water and dried. It was used in the next step without further purification. Yield: 88%.
2-(2,3-Difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (0.500 g) was dissolved in dry DMF (5 mL) and the resulting solution was cooled to 0° C. Aqueous 50% sodium hydroxide (1.5 equivalents) was added and the mixture was stirred for 15 min. Then 5-(chloromethyl)-3-(4-ethoxyphenyl)-isoxazole (1.2 equivalents) was added and the resulting mixture was stirred for 24 h at room temperature. Finally, water (50 mL) was added, the precipitate was collected by filtration and dried to give the crude product.
Recrystallized from ethyl acetate; colorless crystals; yield: 35%
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.2 Hz), 8.28 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.6 Hz), 7.77 (AA′BB′, 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.07-7.00 (m, 3H, arom. H), 6.02 (s, 2H, CH2), 4.06 (q, 2H, OCH2, J=6.9 Hz), 1.32 (t, 3H, CH3, J=6.9 Hz).
The following examples were prepared by analogy to the above procedure:
Figure US08329727-20121211-C00662
Starting from 4-methoxybenzaldehyde.
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.2 Hz), 8.28 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.15 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6 Hz), 7.79 (AA′BB′, 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.09-7.00 (m, 3H, arom. H), 6.01 (s, 2H, CH2), 3.80 (s, 3H, OCH3).
Figure US08329727-20121211-C00663
Starting from 4-methylbenzaldehyde.
1H NMR (200 MHz, DMSO-d6) δ 9.24 (br s, 1H, H4), 8.29 (d, 1H, H6, J=6.7 Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.7 Hz), 7.58-7.27 (m, 6H, arom. H), 7.00 (s, 1H, isoxazole-H), 6.04 (s, 2H, CH2), 2.41 (s, 3H, CH3).
Figure US08329727-20121211-C00664
Starting from 2-furaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.24 (br s, 1H, H4), 8.28 (d, 1H, H6, J=6.7 Hz), 8.15 (m, 1H, phenyl-H), 7.90-7.87 (m, 2H, arom. H), 7.51 (m, 1H, phenyl-H), 7.32 (m, 1H, phenyl-H), 7.15 (d, 1H, furane-H, J=3.6 Hz), 6.96 (s, 1H, isoxazole-H), 6.68 (m, 1H, furane-H), 6.02 (s, 2H, CH2).
Figure US08329727-20121211-C00665
Starting from tiophene-2-carboxaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.6 Hz), 8.27 (dd, 1H, H6, J=7.0, 1.6 Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=7.0 Hz), 7.75-7.70 (m, 2H, arom. H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.19 (dd, 1H, thiophene-H), 7.06 (s, 1H, isoxazole-H), 6.02 (s, 2H, CH2).
Figure US08329727-20121211-C00666
Starting from 4-dimethylaminobenzaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.6 Hz), 8.27 (dd, 1H, H6, J=7.0, 1.6 Hz Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=7.0 Hz), 7.65 (AA′BB′, 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 6.98 (s, 1H, isoxazole-H), 6.76 (AA′BB′, 2H, benzyl-H), 5.75 (s, 2H, CH2), 2.95 (s, 6H, N(CH3)2).
Figure US08329727-20121211-C00667
Starting from 4-biphenylcarboxaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.25 (d, 1H, H4, J=1.6 Hz), 8.30 (dd, 1H, H6, J=7.0, 1.6 Hz Hz), 8.16 (m, 1H, phenyl-H), 7.98-7.70 (m, 7H, arom. H), 7.57-7.26 (m, 5H, arom. H), 7.18 (s, 1H, isoxazole-H), 6.05 (s, 2H, CH2).
Figure US08329727-20121211-C00668
Starting from 4-bromobenzaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.6 Hz), 8.28 (dd, 1H, H6, J=7.0, 1.6 Hz), 8.16 (m, 1H, phenyl-H), 7.90-7.68 (m, 4H, arom. H), 7.51 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.15 (s, 1H, isoxazole-H), 6.05 (s, 2H, CH2).
Figure US08329727-20121211-C00669
Starting from 4benzyloxybenzaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.6 Hz), 8.27 (dd, 1H, H6, J=7.0, 1.6 Hz Hz), 8.15 (m, 1H, phenyl-H), 7.90-7.76 (m, 3H, arom H), 7.57-7.26 (m, 7H, arom. H), 7.15-7.05 (m, 3H, arom. H), 6.01 (s, 2H, N—CH2), 5.16 (s, 2H, O—CH2).
Figure US08329727-20121211-C00670
Starting from 4(methylthio)benzaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.2 Hz), 8.28 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.15 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6 Hz), 7.79 (AA′BB′, 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.38-7.25 (m, 3H, arom. H), 7.10 (s, 1H, isoxazole-H), 6.03 (s, 2H, CH2), 2.51 (s, 3H, SCH3).
Figure US08329727-20121211-C00671
Starting from 2-fluoro-4-methoxybenzaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.26 (d, 1H, H4, J=1.2 Hz), 8.30 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6 Hz), 7.80 (m, 1H, benzyl-H,), 7.49 (mn, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.04-6.71 (m, 3H, arom. H), 6.03 (s, 2H, CH2), 3.82 (s, 3H, OCH3).
Figure US08329727-20121211-C00672
Prepared as described above, starting from 4-chloro-2-fluorobenzaldehyde.
1H NMR (200 MHz, DMSO-d6) □ 9.26 (d, 1H, H4, J=1.4 Hz), 8.30 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.14 (m, 1H, phenyl-H), 7.90-7.87 (m, 2H, arom. H), 7.66 (dd, 1H, arom. H, J=10.8, 1.8 Hz), 7.53-7.41 (m, 2H, arom. H), 7.31 (m, 1H, phenyl-H), 7.10 (d, 1H, isoxazole-H, J=2.7 Hz), 6.06 (s, 2H, CH2).
Figure US08329727-20121211-C00673
Starting from 4-propoxybenzaldehyde
H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.2 Hz), 8.29 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.14 (m, 1H, phenyl-H), 7.88 (d, 1H, H7, J=6.6 Hz), 7.78 (AA′BB′, 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.06-7.00 (m, 3H, arom. H), 6.01 (s, 2H, CH2), 3.97 (t, 2H, OCH2, J=6.5 Hz), 1.73 (hex, 2H, CH2), 0.97 (t, 3H, CH3, J=7.3 Hz).
Figure US08329727-20121211-C00674
Starting from 4-phenoxybenzaldelhyde
1H NMR (200 MHz, DMSO-d6) δ 9.25 (d, 1H, H4, J=1.2 Hz), 8.29 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.16 (m, 1H, phenyl-H), 7.92-7.83 (m, 3H, arom. H), 7.58-7.05 (m, 10H, arom. H), 6.04 (s, 2H, CH2).
Figure US08329727-20121211-C00675
Starting from 1-methylpyrrole-2-carboxaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.2 Hz), 8.28 (dd, 1H, H6, J=6.8, 1.2 Hz), 8.16 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.8 Hz), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 6.98 (dd, 1H, pyrrole-H), 6.92 (s, 1H, isoxazole-H), 6.68 (dd, 1H, pyrrole-H), 6.12 (dd, 1H, pyrrole-H), 6.00 (s, 2H, CH2).
Figure US08329727-20121211-C00676
Starting from 4-isopropoxybenzaldehyde.
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.4 Hz), 8.28 (dd, 1H, H6, J=7.0, 1.4 Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=7.0 Hz), 7.76 (AA′BB′, 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.05-6.98 (m, 3H, arom. H), 6.01 (s, 2H, CH2), 4.67 (hept, 1H, OCH, J=6.2 Hz), 1.26 (d, 6H, (CH3)2, J=6.2 Hz).
Figure US08329727-20121211-C00677
Synthesized as described above, starting from 5-chlorothiophene-2-carboxaldehyde.
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.4 Hz), 8.27 (dd, 1H, H6, J=7.0, 1.4 Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=7.0 Hz), 7.63 (d, 1H, thiophene-H, J=4.0 Hz), 7.51 (m, 1H, phenyl-H), 7.37-7.24 (m, 2H, arom. H), 7.07 (s, 1H, isoxazole-H), 6.03 (s, 2H, CH2).
Figure US08329727-20121211-C00678
Synthesized as described above, staring from 5-bromothiophene-2-carboxaldehyde.
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.4 Hz), 8.27 (dd, 1H, H6, J=6.6, 1.4 Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.6 Hz), 7.59 (d, 1H, thiophene-H, J=3.6 Hz), 7.50 (m, 1H, phenyl-H), 7.36-7.27 (m, 2H, arom. H), 7.06 (s, 1H, isoxazole-H), 6.02 (s, 2H, CH2).
Figure US08329727-20121211-C00679
Synthesized as described above, starting from 4-butoxybenzaldehyde (prepared by alkylation of 4-hydroxybenzaldehyde).
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.2 Hz), 8.28 (dd, 1H, H6, J=6.6, 1.2 Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.6 Hz), 7.78 (AA′BB′, 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 7.07-7.01 (m, 3H, arom. H), 6.01 (s, 2H, CH2), 4.01 (t, 2H, OCH2, J=6.5 Hz), 1.72 (m, 2H, CH2), 1.42 (m, 2H, CH2), 0.93 (t, 3H, CH3, J=7.2 Hz).
Figure US08329727-20121211-C00680
Synthesized as described above, starting from 4-propoxybenzaldehyde and using 2-(2-fluorophenyl)-1(3)H-imidazo[4,5-c]pyridine instead of 2-(2,3-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine.
1H NMR (200 MHz, DMSO-d6) □ 9.18 (d, 1H, H4, J=1.2 Hz), 8.38-8.23 (m, 2H, arom. H), 7.85 (d, 1H, H7, J=6.6 Hz), 7.78 (AA′BB′, 2H, benzyl-H), 7.54-7.25 (m, 3H, phenyl-H), 7.06-7.00 (m, 3H, arom. H), 6.00 (s, 2H, CH2), 3.98 (t, 2H, OCH2, J=6.6 Hz), 1.73 (hex, 2H, CH2), 0.97 (t, 3H, CH3, J=7.3 Hz).
Figure US08329727-20121211-C00681
Starting from 4allyloxybenzaldehyde
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.2 Hz), 8.27 (dd, 1H, H6, J=6.7, 1.2 Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.7 Hz), 7.79 (AA′BB′, 2H, benzyl-H), 7.50 (m, 1H, phenyl-H), 7.31, (m, 1H, phenyl-H), 7.09-7.00 (m, 3H, arom. H), 6.15-5.98 (m, 3H), 5.45-5.24 (m, 2H), 4.62 (d, 2H, J=4.8 Hz).
Figure US08329727-20121211-C00682
A mixture of 5-(chloromethyl)-3-(4-chlorophenyl)-isoxazole (2.00 g), NCS (11.75 g, 10 equivalents), glacial acetic acid (35 mL) and 20 drops of concentrated sulphuric acid is heated to reflux for 3 days. After cooling to room temperature dichloromethane (100 mL) is added, and the resulting mixture is extracted with water (2×100 mL) and saturated aqueous sodium bicarbonate solution (2×100 mL). Then the organic phase was dried over anhydrous sodium sulphate and evaporated. The crude product, thus obtained, was purified by column chromatography (silica gel, eluent: petroleum ether / ethyl acetate=19/1) to give 1.14 g.
The final step was performed as described above. Recrystallized from a mixture of ethyl acetate and ethanol. Yield: 60%.
1H NMR (200 MHz, DMSO-d6) □ 9.20 (d, 1H, H4, J=1.4 Hz), 8.25 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.15 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.8 Hz), 7.83 (AA′BB′, 2H, benzyl-H), 7.66 (AA′BB′, 2H, benzyl-H), 7.51 (m, 1H, phenyl-H), 7.31 (m, 1H, phenyl-H), 6.14 (s, 2H, CH2).
Figure US08329727-20121211-C00683
1H NMR (200 MHz, DMSO-d6) δ 9.18 (d, 1H, H4, J=1.4 Hz), 8.22 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.14 (m, 1H, phenyl-H), 7.89 (d, 1H, H7, J=6.8 Hz), 7.80 (AA′BB′, 2H, benzyl-H), 7.65 (AA′BB′, 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.30 (m, 1H, phenyl-H), 6.11 (s, 2H, CH2).
Synthesized in analogy to the chloroisoxazole derivative 374 u: 4 equ. NBS, 2.5 h reflux, yield: 91%.
Example 375
Figure US08329727-20121211-C00684
To a solution of 500 mg 3-methyl-1-phenylpyrazole in 4 mL carbontetrachloride is added in portions at 70° C. a mixture of 678 mg (1.2 equi.) NBS and AIBN (62.3 mg, 0.12 equ.). The resulting mixture is heated at reflux for an additional 15 minutes and then cooled to room temperature. The precipitate is filtered off and the filtrate is concentrated to precipitate the crude product (380 mg), which—after collecting by filtration and drying—was used in the next step without further purification
The final step was performed as described above. Recrystallized from ethyl acetate. Yield: 35%.
Example 376 imidazo[4,5-c]pyridin-4-one analogues
Figure US08329727-20121211-C00685
A mixture of 4-chloro-3-nitro-pyridin-2-one (1.00 g), 4-(trifluoromethyl)benzyl chloride (1.226 g), anhydrous potassium carbonate (0.871 g) and anhydrous DMF (10 mL) was stirred at ambient temperature for 24 hours. Then water (100 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried. Yield: 58.2% 4-chloro-3-nitro-1-(4-trifluoromethyl)benzyl-pyridin-2-one.
4-Chloro-3-nitro-1-(4-trifluoromethyl)benzyl-pyridin-2-one (500 mg) was dissolved in anhydrous THF (10 mL). Then concentrated aqueous ammonia (7.5 mL) was added and the resulting mixture was stirred at room temperature for 24 hours. Water (50 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried. Yield: 45.8% of 4-amino-3-nitro-1-(4-trifluoromethyl)benzyl-pyridin-2-one.
A mixture of 4-amino-3-nitro-1-(4-trifluoromethyl)benzyl-pyridin-2-one (1.400 g), saturated aqueous ammoniumchloride solution (9.4 mL), zink powder (1.400 g) and methanol (235 mL) was stirred at room temperature for 1 hour. Then additional zink powder (1.400 g) was added and the resulting mixture was stirred for an additional 23 hours. After evaporation of the solvent water (30 mL) was added and the pH was adjusted to 8-9 by addition of 2N NaOH. The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic phases were washed with water (30 mL), dried over anhydrous sodium sulphate and evaporated. Yield: 53.4% 3,4-diamino-1-(4-trifluoromethyl)benzyl-pyridin-2-one.
A mixture of 3,4-diamino-1-(4-trifluoromethyl)benzyl-pyridin-2-one (0.200 mg), 2,3-difluorobenzaldehyde (100 mg), sodium pyrosulfite (0.134 g) and N,N-dimethylacetamide (4.6 mL) was heated at 130° C. for 24 hours. Then water (30 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried. The crude product was purified by column chromatography (silicagel, eluent: dichloromethane/methanol=12/1) and then recrystallized from a mixture of diisopropyl ether and ethyl acetate. Yield: 16.8%. Melting point: 279-283° C.
1H NMR (200 MHz, DMSO-d6) δ 13.05 (br s, 1H, NH), 7.88 (m, 1H, phenyl-H), 7.74-7.32 (m, 7H, arom. H), 6.69 (br d, 1H, H7, J=6.0 Hz), 5.34 (s, 2H, CH2).
Example 377 Synthesis of the 4-methyl analogue 377
Figure US08329727-20121211-C00686
A mixture of 2-(2,3-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine (2.00 g), 50 mg methyltrioxorhenium, 100 mL methanol and 30% aqueous hydrogen peroxide (4 mL) was stirred at room temperature for 4 days. Then, additional 50 mg of methyltrioxorhenium and 30% hydrogen peroxide (4 mL) were added and the resulting mixture was stirred for another 2 days. After evaporation of the methanol water (200 mL) was added and the pH was adjusted to 9 by addition of 2N NaOH. The resulting precipitate was filtered, dried and recrystallized from a mixture of ethyl acetate (20 mL) and ethanol (53 mL) to give 1.208 g (56.5%) of 2-(2,3-difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine 5-oxide.
2-(2,3-Difluorophenyl)-1(3)H-imidazo[4,5-c]pyridine 5-oxide (1.00 g) was dissolved in dry tetrahydrofurane (100 mL) and MeMgBr-solution (14 mL, 3M in diethyl ether) was added dropwise under argon. The resulting mixture was stirred for 1.5 hours at ambient temperature. Then water (100 mL) was added slowly and the pH was adjusted to 8.5. Extraction with ethyl acetate (3×70 mL), drying of the combined organic phases over anhydrous sodium sulphate and evaporation of the solvent afforded 0.630 g (60%) of crude 2-(2,3-difluorophenyl)4-methyl-1(3)H-imidazo[4,5-c]pyridine. Recrystallization from a mixture of diisopropyl ether (20 mL) and ethyl acetate (34 mL) gave 240 mg (24.2%) of pure 2-(2,3-difluorophenyl)-4-methyl-1(3)H-imidazo[4,5-c]pyridine.
The final step was performed as described above. Purification by column chromatography (silica gel, eluent: dichloromethane/methanol=20/1). Yield: 22.4%.
1H NMR (200 MHz, DMSO-d6) δ 8.25 (d, 1H, H6, J=6.8 Hz), 8.11 (m, 1H, phenyl-H), 7.89 (AA′BB′, 2H, benzyl-H), 7.77 (d, 1H, H7, J=6.8 Hz), 7.60-7.41 (m, 3H, arom. H), 7.30 (m, 1H, phenyl-H), 7.12 (s, 1H, isoxazole-H), 6.05 (s, 2H, CH2), 3.05 (s, 3H, CH3).
Example 378 Synthesis of 7-substituted analogues
Figure US08329727-20121211-C00687
Figure US08329727-20121211-C00688
3-Methyl-4-nitropyridine 1-oxide (5.85 g) was dissolved in glacial acetic acid (115 mL) and hydrogenated in a Parr hydrogenation apparatus (catalyst: 220 mg PtO2×2 H2O, 50 psi) at ambient temperature for 2.5 h. Then the catalyst was filtered off and the solvent was evaporated. After addition of 150 mL of water the pH was adjusted to 12 by addition of 2N NaOH. The resulting solution was extracted 10 times with 100 mL of dichloromethane (containing 5% methanol). The combined organic phases were dried over anhydrous sodium sulphate and evaporated to give 3.81 g (83.6%) of 4-amino-3-methylpyridine.
4-Amino-3-methylpyridine (3.00 g) was dissolved with icecooling in concentrated sulfuric acid (36 mL). Then, fuming nitric acid (4,72 g) was added dropwise. After stirring at room temperature for 1 h, the solution was heated at 60° C. for 14 hours. After cooling to ambient temperature, the reaction mixture was poured on ice and the resulting solution was adjusted to pH 13 by addition of solid KOH. The precipitate was filtered off, washed with water and dried. Yield: 1.198 g (31.3%) 4-amino-3-methyl-5-nitropyridine.
A mixture of 4-amino-3-methyl-5-nitropyridine (1.198 g), iron powder (1.748 g), ethanol (52 mL) and hydrochloric acid (13 mL) was heated to reflux for 3 hours. After cooling to room temperature the ethanol was distilled off and the resulting suspension was diluted with water to 50 mL and the pH was adjusted to 13 by addition of 2N NaOH. Extraction with ethyl acetate (3×70 mL), drying of the combined organic phases of anhydrous sodium sulphate and evaporation of the solvent afforded 0.579 g (60%) of 3,4-diamino-5-methylpyridine.
The cyclization with 2,3-difluorbenzoic acid in PPA was performed as described above. Purified by column chromatography (silica gel, eluent: dichloromethan/methanol=12/1). Yield: 22.2%.
The final step was performed as described above. Recrystallized from a mixture of ethyl acetate and ethanol. Yield: 42.9% 378a.
1H NMR (200 MHz, DMSO-d6) δ 9.14 (d, 1H, H4, J=1.2 Hz), 8.17-8.10 (m, 2H, arom. H), 7.90 (AA′BB′, 2H, benzyl-H), 7.60-7.42 (m, 3H, arom. H), 7.32 (m, 1H, phenyl-H), 7.15 (s, 1H, isoxazole-H), 5.99 (s, 2H, CH2), 2.58 (s, 3H, CH3).
The following compounds were prepared in analogy to the above procedures:
Figure US08329727-20121211-C00689
1H NMR (200 MHz, DMSO-d6) δ 9.32 (d, 1H, H4, J=1.4 Hz), 8.67 (d, 1H, H6, J=1.4 Hz), 8.16 (m, 1H, phenyl-H), 7.78 (AA′BB′, 2H, benzyl-H), 7.54 (m, 1H, phenyl-H), 7.34 (m, 1H, phenyl-H), 7.07-7.00 (m, 3H, arom. H), 6.00 (s, 2H, CH2), 4.07 (q, 2H, OCH2, J=7.0 Hz), 1.33 (t, 3H, CH3, J=7.0 Hz).
Figure US08329727-20121211-C00690
1H NMR (200 MHz, DMSO-d6) δ 9.47 (d, 1H, H4, J=1.4 Hz), 8.94 (d, 1H, H6, J=1.4 Hz), 8.16 (m, 1H, phenyl-H), 7.89 (AA′BB′, 2H, benzyl-H), 7.63-7.50 (m, 3H, arom. H), 7.35 (m, 1H, phenyl-H), 7.16 (s, 1H, isoxazole-H), 6.10 (s, 2H, CH2).
Figure US08329727-20121211-C00691
1H NMR (200 MHz, DMSO-d6) δ 9.30 (br s, 1H, H4), 8.66 (dd, 1H, H6, J=7.4, 1.4 Hz), 8.15 (m, 1H, phenyl-H), 7.89 (AA′BB′, 2H, benzyl-H), 7.61-7.47 (m, 3H, arom. H), 7.33 (a, 1H, phenyl-H), 7.16 (s, 1H, isoxazole-H), 6.04 (s, 2H, CH2).
Example 379 1,2,4-oxadiazoles
Figure US08329727-20121211-C00692
A mixture of 4-methoxybenzonitrile (1.00 g), hydroxylamine hydrochloride (0.785 g), KOH (0.640 g) and methanol (20 mL) was heated to reflux for 3 hours. After cooling to room temperature the precipitate was filtered off and the filtrate was evaporated The resulting residue was dissolved in 1N HCl (100 mL) and the resulting solution was extracted with diethyl ether (100 mL). The aqueous phase was neutralized by addition of solid NaHCO3 and extracted with diethyl ether (2×100 mL). The combined organic phases were dried over anhydrous sodium sulphate and evaporated to give 450 mg of the desired amidoxime, which was used without further purification.
A solution of 700 mg of (4-methoxyphenyl)amidoxime and 1.08 g (1.5 equivalents) chloroacetic anhydride in toluene (30 mL) was heated to reflux for 3 hours. After cooling to ambient temperature the reaction mixture was extracted subsequently with water (twice 50 mL), saturated sodium bicarbonate solution (twice 50 mL) and water (50 mL). Finally, the toluene phase was dried over anhydrous sodium sulphate and evaporated to give 660 mg of the desired oxadiazole, which was used without further purification.
The final step was performed as described above (see, for example, isoxazole analogues). Recrystallized from a mixture of ethyl acetate and ethanol. Yield: 35%
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.4 Hz), 8.28 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.15 (m, 1H, phenyl-H), 7.92-7.77 (m, 3H, arom. H), 7.49 (m, 1H, phenyl-H), 7.33 (m, 1H, phenyl-H), 7.08-7.00 (m, 3H, arom. H), 6.01 (s, 2H, CH2), 3.80 (s, 3H, OCH3).
Figure US08329727-20121211-C00693
Prepared as described above, starting from 4-methylbenzonitrile.
1H NMR (200 MHz, DMSO-d6) δ 9.23 (d, 1H, H4, J=1.4 Hz), 8.31 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.14 (m, 1H, phenyl-H), 7.93-7.78 (m, 3H, arom. H), 7.50 (m, 1H, phenyl-H), 7.35-7.27 (m, 3H, arom. H), 6.25 (s, 2H, CH2), 2.35 (s, 3H, CH3).
Figure US08329727-20121211-C00694
Prepared as described above, starting from pyridine-2-carbonitrile.
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.4 Hz), 8.72 (ddd, 1H, pyridine-H), 8.32 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.15 (m, 1H, phenyl-H), 8.00-7.90 (m, 3H, arom. H), 7.64-7.27 (m, 3H, arom. H), 6.30 (s, 2H, CH2).
Figure US08329727-20121211-C00695
Prepared as described above, starting from 4-chlorobenzonitrile.
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.4 Hz), 8.31 (dd, 1H, H6, J=6.8, 1.4 Hz), 8.16 (m, 1H, phenyl-H), 7.96-7.90 (rn, 3H, arom. H), 7.60 (AA′BB′, 2H, benzyl-H), 7.49 (m, 1H, phenyl-H), 7.34 (m, 1H, phenyl-H), 6.28 (s, 2H, CH2).
Figure US08329727-20121211-C00696
Prepared as described above, starting from pyridine-4-carbonitrile.
1H NMR (200 MHz, DMSO-d6) δ 9.24 (d, 1H, H4, J=1.4 Hz), 8.77 (AA′BB′, 2H, pyridine-H2/6), 8.32 (dd, 1H, H6, J=7.0, 1.4 Hz), 8.15 (m, 1H, phenyl-H), 7.93 (d, 1H, H7, J=7.0 Hz), 7.86 (AA′BB′, 2H, pyridine-H3/5), 7.51 (m, 1H, phenyl-H), 7.32 (m, 1H, phenyl-H), 6.32 (s,. 2H, CH2).
Part B Methodology for Determination of Antiviral and Cytostatic Activity
Cells and Viruses
Madin-Darbey Bovine Kidney (MDBK) cells were maintained in Dulbecco's modified Eagle medium (DMEM) supplemented with BVDV-free 5% fetal calf serum (DMEME-FCS) at 37° C. in a humidified, 5% CO2 atmosphere. BVDV-1 (strain PE515) was used to assess the antiviral activity in MDBK cells.
Anti-BVDV Assay
Ninety-six-well cell culture plates were seeded with MDBK cells in DMEM-FCS so that cells reached 24 hr later confluency. Then medium was removed and serial 5-fold dilutions of the test compounds were added in a total volume of 100 μL, after which the virus inoculum (100 μL) was added to each well. The virus inoculum used resulted in a greater than 90% destruction of the cell monolayer after 5 days incubation at 37° C. Uninfected cells and cells receiving virus without compound were included in each assay plate. After 5 days, medium was removed and 90 μL of DMEM-FCS and 10 μL of MTS/PMS solution (Promega) was added to each well. Following a 2 hr incubation period at 37° C. the optical density of the wells was read at 498 nm in a microplate reader. The 50% effective concentration (EC50) value was defined as the concentration of compound that protects 50% of the cell monolayer from virus-induced cytopathic effect.
Anti-HCV Assay/Replicon Assay-1
Huh-5-2 cells [a cell line with a persistent HCV replicon I3891uc-ubi-neo/NS3-3′/5.1; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B HCV polyprotein] was cultured in RPMI medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine (Life Technologies), 1× non-essential amino acids (Life Technologies); 100 IU/mL penicillin and 100 ug/ml streptomycin and 250 ug/mL G418 (Geneticin, Life Technologies). Cells were seeded at a density of 7000 cells per well in 96 well View Plate™ (Packard) in medium containing the same components as described above, except for G418. Cells were allowed to adhere and proliferate for 24 hr. At that time, culture medium was removed and serial dilutions of the test compounds were added in culture medium lacking G418. Interferon alfa 2a (500 IU) was included as a positive control. Plates were further incubated at 37° C. and 5% CO2 for 72 hours. Replication of the HCV replicon in Huh-5 cells results in luciferase activity in the cells. Luciferase activity is measured by adding 50 μL of 1× Glo-lysis buffer (Promega) for 15 minutes followed by 50 μL of the Steady-Glo Luciferase assay reagent (Promega). Luciferase activity is measured with a luminometer and the signal in each individual well is expressed as a percentage of the untreated cultures. Parallel cultures of Huh-5-2 cells, seeded at a density of 7000 cells/well of classical 96-well cell culture plates (Becton-Dickinson) are treated in a similar fashion except that no Glo-lysis buffer or Steady-Glo Luciferase reagent is added. Instead the density of the culture is measured by means of the MTS method (Promega).
Quantitative Analysis of HCV RNA by Taqman Real-Time RT-PCR
Replicon cells were plated at 7.5×103 cells per well in a 96-well plate plates at 37° C. and 5% CO2 in Dulbecco's modified essential medium containing 10% fetal calf serum, 1% nonessential amino acids and 1 mg/ml Geneticin. After allowing 24 h for cell attachment, different dilutions of compound were added to the cultures. Plates were incubated for 5 days, at which time RNA was extracted using the Qiamp Rneazyi Kit (Qiagen, Hilden, Germany). A 50 μL PCR reaction contained TaqMan EZ buffer (50 mmol/L Bicine, 115 mmol/L potassium acetate, 0.01 mmol/L EDTA, 60 mmol/L 6-carboxy-X-rhodamine, and 8% glycerol, pH 8.2; Perkin Elmer Corp./Applied Biosystems), 300 μmol/L deoxyadenosine triphosphate, 300 μmol/L deoxyguanosine triphosphate, 300 μmol/L deoxycytidine triphosphate, 600 μmol/L deoxyuridine triphosphate, 200 μmol/L forward primer [5′-ccg gcT Acc Tgc ccA TTc], 200 μmol/L reverse primer [ccA GaT cAT ccT gAT cgA cAA G], 100 μmol/L TaqMan probe [6-FAM-AcA Tcg cAT cgA gcg Agc Acg TAc-TAMRA], 3 mmol/L manganese acetate, 0.5 U AmpErase uracil-N-glycosylase, 7.5 U rTth DNA polymerase, and 10 μl of RNA elution. After initial activation of uracil-N-glycosylase at 50° C. for 2 minutes, RT was performed at 60° C. for 30 minutes, followed by inactivation of uracil-N-glycosylase at 95° C. for 5 minutes. Subsequent PCR amplification consisted of 40 cycles of denaturation at 94° C. for 20 seconds and annealing and extension at 62° C. for 1 minute in an ABI 7700 sequence detector. For each PCR run, negative template and positive template samples were used. The cycle threshold value (Ct-value) is defined as the number of PCR cycles for which the signal exceeds the baseline, which defines a positive value. The sample was considered to be positive if the Ct-value was <50. Results are expressed as genomic equivalents (GE).
Anti-HCV Assay/Replicon Assay-2
  • HCV Replicon Media
  • DMEM w/High Glucose (or MEM)
  • 1× Glutamine
  • 1× Sodium Pyruvate
  • 10% Heat Inactivated FBS
  • 1× Antibiotics
    Cell Culture Preparation
  • 1. Unthaw frozen stock in 10-12 mls of Media
  • 2. Allow cells to attach before adding G418 (4-6 hrs)
  • 3. Add G418 for a final concentration of 200 ug/mL (higher amounts are possible but cells grow slowly)
  • 4. Split cells 1:4 to 1:6 for optimal growth
  • 5. In-house replicon seems to maintain Luciferase signal for ˜20 passages
    HCV Replicon Assay
  • 1. Dilute compounds in 100 uL of HCV Replicon Media (without G418). If compounds are diluted in DMSO add DMSO to media (Final DMSO concentration should be <1%)
  • 2. Once cells have reached 80-90% confluency, trypsinize with 1× Trypsin
  • 3. Do not over trypsinize. These cells tend to clump if over trypsinized
  • 4. For 96 well format add 6,000-8,000 cells per well (G418 is withheld during compound testing)
  • 5. Incubate for 3 days at 37° C. Cells should be very close to confluent.
  • 6. Remove media and wash cells with 1× PBS
  • 7. Remove PBS and add 100 μL of 1× Promega Lysis Buffer
  • 8. Incubate cells at Room Temperature for 5-20 minutes
  • 9. Add 100 μL of room temperature Luciferase Substrate Solution (Promega) to Microfluor Black Plate (VWR)
  • 10. Thoroughly Mix Cell lysate (pipet up and down) before adding to Luciferase substrate
  • 11. Add 75 μL of lysate to the Luciferase substrate solution
  • 12. Read Plate On Top Count (FusionLucB program ˜5 second read)
  • 13. Left over lysate can be frozen and used for later analysis
    Determination of Cytostatic Effect on MDBK Cells
The effect of the drugs on exponentially growing MDBK cells was assessed as follows. Cells were seeded at a density of 5000 cell/well in 96 well plates in MEM medium (Gibco) supplemented with 10% fetal calf serum, 2 mM L-glutamine (Life Technologies) and bicarbonate (Life Technologies). Cells were cultured for 24 hr after which serial dilutions of the test compounds were added. Cultures were then again further incubated for 3 days after which the effect on cell growth was quantified by means of the MTS method (Promega). The concentration that results in 50% inhibition of cell growth is defined as the 50% cytostatic concentration (CC50)
HCV CC50 Assay Protocol
  • HCV Replicon Media
    DMEM w/High Glucose (or MEM)
  • 1× Glutanine
  • 1× Sodium Pyruvate
  • 10% Heat Inactivated FBS
  • 1× Antibiotics
    Cell Culture Preparation
  • 1. Unthaw frozen stock in 10-12 mls of Media
  • 2. Allow cells to attach before adding G418 (4-6hrs)
  • 3. Add G418 for a final concentration of 200 ug/ml (higher amounts are possible but cells grow slowly)
  • 4. Split cells 1:4 to 1:6 for optimal growth
  • 5. In-house replicon seems to maintain Luciferase signal for ˜20 passages
    HCV Replicon Assay
  • 1. Dilute compounds in 100 uL of HCV Replicon Media (without G418). If compounds are diluted in DMSO add DMSO to media (Final DMSO concentration should be <1%)
  • 2. Once cells have reached 80-90% confluency, trypsinize with 1× Trypsin
  • 3. Do not over trypsinize. These cells tend to clump if over trypsinized
  • 4. For 96 well format add 6,000-8,000 cells per well (G418 is withheld during compound testing)
  • 5. Incubate for 3 days at 37° C. Cells should be very close to confluent.
  • 6. Remove media and add 200 μL of a 0.2 mg/mL MTT solution prepared in media.
  • 7. Incubate for 1.5 hours to 2 hours.
  • 8. Remove media and add 150 μL of DMSO
  • 9. Mix and incubate for 5 mins at room temperature
  • 10. Read plate at 530 nm in the plate reader.
    Results
The compounds of Examples 2, 3A, 4 and 5 were found to have an EC50 in Replicon assay 2 of, respectively in micromoles, 0.01, 0.02, 0.01 and 0.0039, and to have a CC50 in the CC50 assay protocol of, respectively in micromoles, 26, 34, 19 and 10.8 (replicate 13.4).
Substantially all of the compounds in Table 1 demonstrated activity of at least 1 micromolar in an anti-HCV/Replicon assay system. In addition, a number of the compounds also exhibited anti-BVDV activity.

Claims (37)

1. A method of treating a viral infection from a virus belonging to the family of the Flaviviridae or the Picornaviridae, said method comprising administering to a subject in need of treatment an anti-virally effective amount of (i) a compound having the structural formula (A),
Figure US08329727-20121211-C00697
wherein:
the dotted lines represent an optional double bond, provided that no two double bonds are adjacent to one another, and that the dotted lines represent at least 3 double bonds;
R1 is selected from the group consisting of aryl, heterocycle, C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkyl-amino, C1-C10 dialkylamino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each is optionally substituted with one or more R6;
Y is selected from a single bond, O, S(O)m, NR11, C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene, wherein each alkylene, alkenylene or alkynylene optionally includes 1 to 3 heteroatoms selected from O, S or N;
R2 and R4 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, —SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, and heterocycle, or when one of R25 or R26 is present, R2 or R4 is selected from the group consisting of (═O), (═S), and ═NR27;
X is selected from the group consisting of C1-10 alkylene, C2-10 alkenylene and C2-10 alkynylene, where each optionally includes one or more heteroatoms selected from the group consisting of O, S, or N, provided any such heteroatom is not adjacent to the N in the imidazopyridyl ring;
m is any integer from 0 to 2;
R3 is a heterocycle substituted with one or more R17, provided that R3 optionally substituted with at least one R17 is not pyridinyl or 5-chlorothienyl;
R5 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)R9, —C(═S)R9, SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, and heterocycle;
each R6 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —CO2R18, —NO 2, —NR7R8, C1-18 haloalkyl, —C(═O)R18, —C(═S)R18, —SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, heterocycle and C1-18 hydroxyalkyl, where each is optionally substituted with one or more R19;
R7 and R8 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12; —C(═S) R12, and an amino acid residue linked through a carboxyl group thereof, or R7 and R8 are taken together with the nitrogen to form a heterocycle;
R9 and R18 are independently selected from the group consisting of hydrogen, —OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16, aryl, an amino acid residue linked through an amino group of the amino acid, —CH2OCH(═O)R9a, and —CH2OC(═)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
R11 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═)R12, heterocycle, and an amino acid residue;
R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, and an amino acid residue;
R15 and R16 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, and an amino acid residue;
each R17 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C2-18 halogenated alkenyl, C2-18 halogenated alkynyl, C2-18 halogenated alkoxy, C1-18 halogenated alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, OH, CN, NO2, NR7R8, haloalkyl, C(═)R18, C(═S)R18, SH, aryl, aryloxy, arylthio, CO2H, CO2R18, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl, arylalkyloxy, arylalkylthio, heterocyclic, and C1-18 hydroxyalkyl, where each of said aryl, aryloxy, arylthio, arylalkyl, arylalkyloxy, arylalkylthio, heterocycle, C1-18 hydroxyalkyl, arylsulfoxide, arylsulfone, or arylsulfonamide is optionally substituted with one or more R19;
each R19 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═S )R18, -OalkenylC(═O)OR18, -OalkylC(═O)NR20R21, -OalkylOC(═O)R18, —C(═S)R18, SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocycle, C1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18 alkyl)oxy, arylthio, aryl(C1-18)alkylthio and aryl(C1-18)alkyl, where each is optionally substituted with 1 or more ═O, —NR20R21, —CN, C1-18 alkoxy, heterocycle, C1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R17 by alkyl, alkoxyalkoxy or halogen;
R20 and R21 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, carboxylester-substituted heterocycle, and —C(═S)R12;
R25 and R26 are not present, or are independently selected from the group consisting of hydrogen, C1-18 alkyl, C3-10 cycloalkyl, aryl and heterocycle, where each is optionally independently substituted with 1 to 4 of C1-6 alkyl, C1-6 alkoxy, halo, —CH2OH, benzyloxy, and —OH; and
R27 is selected from the group consisting of hydrogen, C1-18 alkyl, C3-10 cycloalkyl, (C3-10 cycloalkyl)—C1-6 alkyl, aryl, and aryl(C1-18)alkyl; and salts, tautomers, and stereoisomers thereof;
or (ii) a compound having the structural formula (C),
Figure US08329727-20121211-C00698
wherein:
R1 is selected from the group consisting of aryl, heterocycle, C1-C10 alkoxy, C1-C10 thioalkyl, C1-C10 alkyl-amino, C1-C10 dialkylamino, C3-10 cycloalkyl, C4-10 cycloalkenyl, and C4-10 cycloalkynyl, wherein each is optionally substituted with one or more R6;
Y is selected from a single bond, O, S(O)m, NR11, C1-10 alkylene, C2-10 alkenylene, or C2-10 alkynylene, wherein each alkylene, alkenylene or alkynylene optionally includes 1 to 3 heteroatoms selected from O, S or N;
R2 and R4 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═S)R9, —SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, and heterocycle;
X is selected from the group consisting of C1-C10 alkylene, C2-10 alkenylene and C2-10 alkynylene, where each optionally includes one or more heteroatoms selected from the group consisting of O, S, or N, provided any such heteroatom is not adjacent to the N in the imidazopyridyl ring;
m is any integer from 0 to 2;
R3 is aryl, aryloxy, arylthio, cycloalkyl, cycloalkenyl, cycloalkynyl,)aryl-N(R10 )—, or heterocycle, each of which is optionally substituted with one or more R17, provided that for cycloalkenyl the double bond is not adjacent to a nitrogen, provided M-Q-R3 is not biphenyl, and provided that R3 substituted with at least one R17 is not pyridinyl or 5-chlorothienyl;
R5 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, halogen, —OH, —CN, —NO2, —NR7R8, haloalkyloxy, haloalkyl, —C(═O)R9, —C(═O)OR9, —C(═S)R9, —SH, aryl, aryloxy, arylthio, arylalkyl, C1-18 hydroxyalkyl, C3-10 cycloalkyl, C3-10 cycloalkyloxy, C3-10 cycloalkylthio, C3-10 cycloalkenyl, C7-10 cycloalkynyl, and heterocycle;
each R6 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C1-18 alkylthio, C1-18 alkylsulfoxide, C1-18 alkylsulfone, C1-18 halo-alkyl, C2-18 halo-alkenyl, C2-18 halo-alkynyl, C1-18 halo-alkoxy, C1-18 halo-alkylthio, C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —CO2R18, —NO2, —NR7R8, C1-18 haloalkyl, —C(═O)R18, —C(═S)R18, —SH, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, aryl(C1-18)alkyl, aryl(C1-18)alkyloxy, aryl(C1-18)alkylthio, heterocycle and C1-18 hydroxyalkyl, where each is optionally substituted with one or more R19;
R7 and R8 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, heterocycle, —C(═O)R12; —C(═S) R12, and an amino acid residue linked through a carboxyl group thereof, or R7 and R8 are taken together with the nitrogen to form a heterocycle;
R9 and R18 are independently selected from the group consisting of hydrogen, —OH, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, C1-18 alkoxy, —NR15R16 , aryl, an amino acid residue linked through an amino group of the amino acid, —CH2OCH(═O)R9a, and —CH2OC(═O)OR9a where R9a is C1-C12 alkyl, C6-C20 aryl, C6-C20 alkylaryl or C6-C20 aralkyl;
R10and R11 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocycle, and an amino acid residue;
R12 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, and an amino acid residue;
R15 and R16 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, and an amino acid residue;
each R17 is independently MQ- wherein M is a ring optionally substituted with one or more R19, and Q is a bond or a linking group connecting M to R3 that has 1 to 10 atoms and is optionally substituted with one or more R19;
each R19 is independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, C1-18 alkoxy, C2-18 alkenyloxy, C2-18 alkynyloxy, C1-18 alkylthio, C3-10 cycloalkyl, C4-10 cycloalkenyl, C4-10 cycloalkynyl, halogen, —OH, —CN, cyanoalkyl, —NO2, —NR20R21, C1-18 haloalkyl, C1-18 haloalkyloxy, —C(═O)R18, —C(═O)OR18 , -OalkenylC(═O)OR18, -OalkylC(═O)NR20R21, -OalkylOC(═O)R18, —C(═S)R18, —SH, —C(═O)N(C1-6 alkyl), —N(H)S(O)(O)(C1-6 alkyl), aryl, heterocycle, C1-18 alkylsulfone, arylsulfoxide, arylsulfonamide, aryl(C1-18)alkyloxy, aryloxy, aryl(C1-18 alkyl)oxy, arylthio, aryl(C1-18)alkylthio and aryl(C1-18)alkyl, where each is optionally substituted with 1 or more ═O, —NR20R21, —CN, C1-18 alkoxy, heterocycle, C1-18 haloalkyl, heterocycle alkyl, heterocycle connected to R17 by alkyl, alkoxyalkoxy or halogen;
R20 and R21 are independently selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C2-18 alkynyl, aryl, C3-10 cycloalkyl, C4-10 cycloalkenyl, —C(═O)R12, and —C(═S)R12; and
salts, tautomers, and stereoisomers thereof.
2. The method of claim 1, wherein the viral infection is an infection of a hepatitis-C virus.
3. The method of claim 1, further comprising administering at least one additional antiviral therapy to the subject.
4. The method of claim 3, wherein the additional therapy is selected from the group consisting of an interferon alpha and ribavirin.
5. The method of claim 1, wherein the viral infection is an infection from a Coxsackie virus.
6. The method of claim 1, wherein the viral infection is an infection from a Bovine Viral Diarrhea Virus.
7. The method of claim 1, wherein the compound of formula (A) is administered.
8. The method of claim 7, wherein, in the compound of formula (A), R3 is isoxazolyl substituted with one to three R17.
9. The method of claim 7, wherein, in the compound of formula (A), YR1 is halophenyl or halomethyl-substituted phenyl.
10. The method of claim 9, wherein halophenyl is ortho-fluorophenyl.
11. The method of claim 7, wherein, in the compound of formula (A), R17 is aryl or a heterocycle further substituted with 1, 2 or 3 R19.
12. The method of claim 7, wherein, in the compound of formula (A), YR1 is not an unsubstituted C3-10 cycloalkyl.
13. The method of claim 7, wherein, in the compound of formula (A), R19 is trihalomethyl, trihalomethoxy, alkoxy or halogen.
14. The method of claim 7, wherein, in the compound of formula (A), R1 is aryl or aromatic heterocyle substituted with 1, 2 or 3 R6 and wherein R6 is halogen, C1-18 alkoxy or C1-18 haloalkyl.
15. The method of claim 7, wherein, in the compound of formula (A), Y is a bond.
16. The method of claim 7, wherein, in the compound of formula (A), X is selected from the group consisting of —CH2—, —CH(CH3)—,—CH2—CH2—, —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2, —(CH2)2-4—O—(CH2)2-4—, —(CH2)2-4S—(CH2)2-4—,—(CH2)2-4—NR10—(CH2)2-4), C3-10 cycloalkylidene, C2-6 alkenylene and C2-6 alkynylene, wherein R1 is selected from the group consisting of hydrogen, C1-18 alkyl, C2-18 alkenyl, C3-10 cycloalkyl, C4-10 cycloalkenyl, aryl, —C(═O)R12, heterocyclic, and an amino acid residue.
17. The method of claim 7, wherein, in the compound of formula (A), X is methylene.
18. The method of claim 7, wherein, in the compound of formula (A), R3 is a heterocycle substituted with 0 to 3 R17.
19. The method of claim 18, wherein the R3 is an aromatic heterocycle.
20. The method of claim 19, wherein the heterocycle contains 1, 2 or 3 N, S or O atoms in the ring, is linked to X through a ring carbon atom and contains 4 to 6 total ring atoms.
21. The method of claim 7, wherein, in the compound of formula (A), R17 is selected from the group consisting of C3-10 cycloalkyl, C3-10 cycloalkenyl, C7-10 cycloalkynyl, aryl, aryloxy, arylthio, arylsulfoxide, arylsulfone, arylsulfonamide, arylalkyl; arylalkyloxy; arylalkylthio and heterocycle, each being unsubstituted or substituted with 1 or more R19.
22. The method of claim 7, wherein, in the compound of formula (A), R9 and R18 are H, OH or alkyl.
23. The method of claim 7, wherein, in the compound of formula (A), R5 is H.
24. The method of claim 7, wherein, in the compound of formula (A), R6 is halogen.
25. The method of claim 7, wherein, in the compound of formula (A), R7, R8, R11, R15 ,R16,R20 and R21 are independently H or C1-18 alkyl.
26. The method of claim 7, wherein, in the compound of formula (A), R12 is alkyl.
27. The method of claim 7, wherein, in the compound of formula (A), R19 is selected from the group consisting of H; C1-18 alkyl; C2-18 alkenyl; C2-18 alkynyl; C1-18 alkoxy; alkenyloxy; alkynyloxy; C1-18 alkylthio; C3-10 cycloalkyl; C4-10 cycloalkenyl; C4-10 cycloalkynyl; halogen; OH; CN; cyanoalkyl; NO2; NR20R21; haloalkyl; haloalkyloxy; C(═O)R18; C(═O)OR18; OalkenylC(═O)OR18; -OalkylC(═O)NR20R21; aryl; heterocycle; -OalkylOC(═O)R18; C(═O)N(C1-6alkyl), N(H)S(O)(O)(C1-6 alkyl); arylalkyloxy; aryloxy; arylalkyloxy; and arylalkyl; each of which is unsubstituted or substituted with 1 or more ═O; NR20R21; CN; alkoxy; heterocycle; C1-18 haloalkyl; heterocycle alkyl; heterocycle linked to R17 by alkyl; alkoxyalkoxy or halogen.
28. The method of claim 27, wherein R19 is independently selected from the group consisting of halogen, NR20R21, alkoxy, haloalkyl and haloalkyloxy.
29. The method of claim 7, wherein, in the compound of formula (A), R25 and R26 are not present.
30. The method of claim 7, wherein, in the compound of formula (A), haloalkyl or haloalkyloxy is —CF3 or —OCF3.
31. The method of claim 7, wherein, in the compound of formula (A), Y is a single bond, and R1 is phenyl.
32. The method of claim 1, wherein the compound of formula (C) is administered.
33. The method of claim 32, wherein, in the compound of formula (C), Y is a single bond, and R1 is aryl.
34. The method of claim 32, wherein, in the compound of formula (C), X is C1-C10alkylene, C2-10 alkenylene or C2-10 alkynylene.
35. The method of claim 32, wherein, in the compound of formula (C), R3 is a heterocyle.
36. The method of claim 32, wherein, in the compound of formula (C), R3 is a heterocycle substituted with R17 where Q is a bond and M is aryl.
37. The method of claim 32, wherein, in the compound of formula (C), R3 is isoxazole substituted with R17 where Q is a bond and M is aryl.
US12/577,865 2003-12-22 2009-10-13 Imidazo[4,5-c]pyridine compounds and methods of antiviral treatment Active 2026-03-25 US8329727B2 (en)

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